Bone serves as a specialized, mineralized connective tissue that provides protection, mechanical support to internal tissues, houses the bone marrow, and permits locomotion (Robling et al., 2006). Despite its seemingly static nature, bone is a highly dynamic organ that undergoes continuous remodeling throughout life. Bone remodeling relies on the coordinated activity of osteoclasts, which resorb old or damaged bone, and osteoblasts, which produce and deposit new bone matrix (Sims and Gooi, 2008; Matsuo and Irie, 2008).

Osteoblasts derive from mesenchymal stem cells (MSCs) and account for 4–6% of the total resident cells in bone (Capulli et al., 2014). Their primary function is the production of bone matrix by secretion of type I collagen and proteoglycans and the subsequent mineralization (Florencio-Silva et al., 2015; Downey and Siegel, 2006). Mature osteoblasts can either undergo apoptosis (Jilka et al., 1998), become embedded in the matrix as osteocytes (Compton and Lee, 2014), or transition into bone lining cells (Miller and Jee, 1987).

Osteoclasts come from a different cell source, originating from mononuclear cells of the hematopoietic lineage (Crockett et al., 2011; Asagiri and Takayanagi, 2007), which upon differentiation and activation form large, multinucleated, highly motile cells that carry out their bone resorption activity. Actively resorbing osteoclasts polarize and their plasma membrane assumes a folded appearance when in contact with bone surface, known as the ruffled border. Within the ruffled border, vacuolar-type H+-ATPase (V-ATPase) and chloride channels contribute to acidifying the extracellular environment, enabling the dissolution of hydroxyapatite crystals (Stenbeck, 2002). This process is further facilitated by enzymes such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase-9 (MMP-9), which are released into the Howship lacuna (Ljusberg et al., 2005; Mulari et al., 2003). Degradation products are subsequently endocytosed across the ruffled border and transcytosed to the functional exit site on the opposite side of the cell, where they are secreted (Arana-Chavez and Bradaschia-Correa, 2009).

Osteoblast-mediated bone formation and osteoclast-mediated bone resorption are tightly coupled processes, in which both cell types continuously communicate to preserve bone homeostasis. Imbalances in this delicate equilibrium are associated with various bone diseases, including osteoporosis and osteogenesis imperfecta (Seeman, 2003; Etich et al., 2020). While it has long been recognized that osteoblasts can regulate osteoclast differentiation and activity through direct cell–cell communication or by release of soluble factors (Chen et al., 2018; Phan et al., 2004; Boyce, 2013; Martin, 2004), questions regarding how osteoblasts are recruited to the sites of bone remodeling and how they can produce the appropriate amount of bone remained unanswered for a considerable time.

In the last decades, advancements in the understanding of certain cellular events and pathways have shed new light on the osteoclast’s ability to promote and direct bone formation. Such positive correlation between systemic bone resorption and bone formation has been defined as ‘coupling’. The coupling mechanism is necessary to achieve termination of osteoclastic bone resorption and consequent osteoblastic bone formation to fill resorption lacunae with new bone (Sims and Martin, 2014).

Interactions between membrane-bound receptors located on osteoclast and osteoblast surfaces, as well as matrix-derived factors released during bone resorption can drive bone formation to the required sites. More recently, it has become evident that several osteoclast-secreted coupling factors, known as clastokines, also play a role in preserving bone homeostasis by influencing osteoblast differentiation and activity. Techniques such as Alizarin Red staining and evaluation of Alkaline Phosphatase activity in osteoblast cultures treated with osteoclast conditioned media, together with the analysis of bone parameters in osteoclast-specific conditional knockout mouse models, have demonstrated that these factors are able to promote osteoblast differentiation and mineralization in vitro and in vivo, thereby expanding the known functions of osteoclasts (Drissi and Sanjay, 2016; Cappariello et al., 2014).

This review offers an integrated perspective on the active role of osteoclasts as regulators of bone formation, beyond their conventional role as bone-resorbing cells. We will thoroughly explore the currently known coupling factors and clastokines, discussing their functions, mechanism of activity, and their impact on bone homeostasis. Recognizing how osteoclasts actively collaborate with other members of the bone multicellular unit (BMU) is not only critical to better understand bone homeostasis but also presents an opportunity for the identification of new therapeutic targets for the treatment of bone diseases.

It has long been acknowledged that bone matrix harbors various osteotropic factors that, upon release during osteoclastic bone resorption, can directly or indirectly affect the bone formation activity of osteoblasts. Indeed, growth factors released from the matrix were the first to be identified as coupling factors.

A significant factor impacted by bone resorption is latent, matrix-bound transforming growth factor-β1 (TGF-β1), which becomes activated and released by osteoclasts (Figure 1). Latent mature TGF-β is covalently linked to its latency-associated propeptide (LAP) in the matrix. This small complex can further become associated with a latent TGF-β-binding protein (LTBP) (Janssens et al., 2005). Bone resorption by osteoclasts can contribute to creating an acidic environment able to activate TGF-β (Oreffo et al., 1989), but also induces the release of several proteases, such as matrix metalloproteinases (MMPs), Bone morphogenetic protein 1 (BMP-1), and serine proteases that cleave either LAP or LTBP, liberating active TGF-β (Dallas et al., 2002; Ge and Greenspan, 2006).

Figure 1

Download asset Open asset

Active TGF-β1 has been shown to directly induce migration of osteoprogenitors toward bone remodeling sites (Tang et al., 2009; Ota et al., 2013b). In this study, bone MSCs were observed to migrate in response to a TGF-β1 gradient, exhibiting typical lamellipodia-like protrusions, in a process mediated by SMAD signaling (Tang et al., 2009). Besides its direct effects on osteoblasts, TGF-β1 also stimulates osteoclasts to secrete several coupling factors. Notably, TGF-β1-mediated SMAD2/3 signaling stimulates the release of WNT10B by osteoclasts to promote its clastokine activity, as demonstrated by reduced bone formation in response to TGF-β administration in presence of the WNT inhibitor dickkopf-1 (DKK-1) (Ota et al., 2013a). Additionally, TGF-β1 was shown to increase osteoclast expression of the chemokine C-X-C motif chemokine ligand 16 (CXCL16), further enhancing osteoblast migration to recover from bone loss due to bone resorption (Ota et al., 2013b). At the same time, TGF-β1 was also shown to directly stimulate leukemia inhibitory factor (LIF) expression through MEK and SMAD2/3 activation (Ota et al., 2013b). LIF, previously described to act synergistically with TGF-β to promote cell survival (Marzella et al., 1999), opposed direct TGF-β1-mediated stimulation of osteoblast migration (Ota et al., 2013b), pointing out a fine regulation of TGF-β activity in bone metabolism. Taken together, these findings highlight the coupling role of TGF-β in activating osteoblast precursors both directly and through stimulation of several clastokines in osteoclasts during bone resorption.

At bone remodeling sites, the exposed bone matrix creates a stiff and elastic microenvironment capable to drive osteoblast differentiation (Engler et al., 2006). At these locations, other factors are present and can participate in promoting differentiation into osteoblasts.

Insulin-like growth factor 1 (IGF-1), the predominant growth factor in the bone matrix, is stored in the matrix bound to the regulatory protein insulin-like growth factor-binding protein (IGFBP) (Crane and Cao, 2014). IGF-1 can be activated after cleavage of IGFBP by MMPs, BMP-1, and ADAM-9 secreted by osteoblasts upon resorption of bone matrix by osteoclasts. If osteoclasts also release IGFBP proteases is still unclear (Figure 1; Crane and Cao, 2014; Thrailkill et al., 1995; Kim et al., 2011; Mohan et al., 2002). Active IGF-1 induces osteoblastic differentiation of MSCs through the activation of the mTOR signaling pathway (Xian et al., 2012). IGFBP3 regulates IGF-1 lifespan, mediating the incorporation of circulating IGF-1 in the bone matrix to carry out its role during bone remodeling (Xian et al., 2012). Interestingly, in vivo studies have revealed a direct correlation between IGF-1 concentration and bone mass, which declines with age (Xian et al., 2012), suggesting a potential role for IGF-1 in the maintenance of bone mass throughout life.

Osteoblasts are known to regulate osteoclast differentiation by direct cell–cell communication through membrane-bound receptors, for example through the tumor necrosis factor receptor superfamily member 6 (FAS) ligand (FASL)–FAS axis (Wang et al., 2015). However, the capability of osteoclasts to control osteoblast differentiation through direct cell–cell interaction remains understudied. Conventional bone histomorphometric analyses have not been able to show direct binding between these two cell types, resulting in the traditional view of bone remodeling within the BMU as a sequential process, in which bone forming and bone resorptive activities are thought not to occur together but are spatiotemporally distinct from each other (Hattner et al., 1965). However, the advent of cutting-edge technologies, such as intravital two-photon microscopy, has demonstrated that contact areas between osteoblasts and osteoclasts are indeed present and play vital roles in bone homeostasis, even if the mechanisms remain elusive (Furuya et al., 2018). Below we provide examples of recent data describing signaling through direct cell–cell contact between osteoclasts and osteoblasts to change each other’s activity and function. While there is clear evidence for such signaling mechanisms, further research needs to be performed in order to understand their specific spatiotemporal occurrence.

Erythropoietin-producing hepatocellular carcinoma tyrosine kinase receptors (EPH) and their membrane-bound ligands, the Ephrins (EFN), play important roles in development and homeostasis, including axon guidance and angiogenesis (Pasquale, 2010). Ephrin B2 (EFNB2) and its receptor EPHB4 are an example of molecules able to mediate osteoclast–osteoblast interaction by simultaneous signal transduction in both cell types, resulting in bidirectional signaling. In reverse signaling (osteoblast to osteoclast), the interaction between EPHB4, located on osteoblasts, and EFNB2 on osteoclasts has been demonstrated to suppress osteoclastogenesis by blocking the c-Fos-NFATc1 cascade (Zhao et al., 2006; Figure 2). Conversely, in forward signaling (osteoclast to osteoblast), EFNB2 activates tyrosine phosphorylation-dependent EPHB4 signaling in osteoblast precursors, promoting osteoblast differentiation and preventing apoptosis, likely through attenuated RhoA activity (Zhao et al., 2006; Tonna et al., 2014). Transgenic mice overexpressing EPHB4, characterized by increased femoral bone density, confirmed this mechanism in vivo (Zhao et al., 2006).

Figure 2

Download asset Open asset

Conditional deletion of Bone Morphogenetic Protein Receptor 1 (BMPR1) in murine osteoclasts revealed an interesting possible pathway for osteoclast–osteoblast communication requiring direct cell–cell contact. Loss of BMPR1 was shown to result in increased bone formation due to increased levels of its downstream target Connexin 43 (CX43/GJA1), a gap junction protein with a critical role as positive regulator of both osteoblast and osteoclast differentiation (Ilvesaro et al., 2000; Watkins et al., 2011; Ransjö et al., 2003). Gap junctions are important propagators of anabolic signals and agents such as parathyroid hormone (PTH) (Chung et al., 2006). This finding allows to speculate that CX43 permits trafficking of small molecules that act as coupling factors from osteoclasts to osteoblasts and point out BMPR1 as a negative regulator of osteoclast-induced bone formation (Okamoto et al., 2011; Shi et al., 2017), but further studies are required to better understand how the direct cell–cell contact event unfolds.

Traditionally, the coupling mechanism is associated with the promotion of bone anabolism by osteoclasts. However, osteoclast-derived signals do not always connect bone resorption to bone formation; in some cases, they can separate the two activities.

An inhibitory role has been described for Semaphorin 4D (SEMA4D), a transmembrane protein strongly expressed in osteoclasts but not in osteoblasts (Dacquin et al., 2011; Negishi-Koga et al., 2011). While SEMA4D can be partially secreted as a soluble factor, its membrane-bound form plays a more significant role in bone communication (Negishi-Koga et al., 2011). Likely during the initiation phase of bone remodeling, SEMA4D binds to a receptor complex on osteoblasts consisting of Plexin-B1 and erythroblastic leukemia viral oncogene homolog 2 (ErbB2). The interaction leads to the activation and autophosphorylation of ErbB2, which in turn phosphorylates Plexin-B1. The subsequent activation of RhoA–Rho-associated protein kinase (ROCK) pathway leads to reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), a positive regulator of osteogenesis (Wang et al., 2018; Xi et al., 2019), thus resulting in inhibited bone formation (Negishi-Koga et al., 2011). SEMA4D signaling also promotes osteoblast motility away from the sites of resorption by decreasing cadherin-11 expression (Negishi-Koga et al., 2011). Due to its inhibitory role, SEMA4D has been suggested not to be classified as a coupling factor, but rather as a bone communication factor important for intercellular crosstalk during bone remodeling (Negishi-Koga and Takayanagi, 2012).

The concept that osteoclasts might secrete factors promoting osteoblast differentiation is not recent. Scientists began speculating about the existence of osteoclast-derived coupling factors as early as the 1980s (Farley et al., 1987), with more focused efforts initiated in the early 2000s (Martin and Sims, 2005; Karsdal et al., 2008; Karsdal et al., 2007). In 2008, the discovery that conditioned media from human osteoclasts was able to induce bone nodule formation by osteoblasts in a dose-dependent manner sparked further investigation into the mechanisms underlying osteoclastic control of osteoblasts (Karsdal et al., 2008). To this effect, molecules secreted by osteoclasts that demonstrated the ability to influence osteoblastic activity or function have widely been termed ‘clastokines’, and their roles have started to be explored both in vitro and in vivo (Figure 2, Table 1).

Indeed, Sphingosine-1-phosphate (S1P) was one of the initially identified clastokines. S1P is a bioactive lysosphingolipid playing fundamental roles in morphogenesis, including tissue induction, collective cell migration, and biomechanical signaling (Mendelson et al., 2014). It is produced by osteoclasts through sphingosine phosphorylation by Sphingosine kinase 1 (SPHK1) and exerts its functions by interacting with its receptors located on the membrane of several cell types (Figure 2). S1P importance for bone homeostasis comes not only from its capability to control migration and behavior of osteoclast precursors (Ishii et al., 2009), but also from its uncovered role as a clastokine.

During osteoclast differentiation, increased SPHK1 expression and activity lead to high S1P levels (Ryu et al., 2006). S1P is then released from osteoclasts to the extracellular space through the transmembrane transporter SPNS2. S1P was shown to promote migration of MSCs in vitro through activation of the JAK/STAT3 and FAK/PI3K/AKT signaling pathways mediated by its receptors S1PR₁ and S1PR₂, respectively (Quint et al., 2013). Moreover, S1P enhances bone formation in vivo by binding to its osteoblast receptor S1PR₃ (Pederson et al., 2008; Keller et al., 2014). In a different in vitro study, S1P signaling activated extracellular-signal regulated kinases (ERK) and p38, which upregulated cyclooxygenase-2 (COX2) levels, resulting in increased prostaglandin E₂ (PGE2) production and subsequent enhanced Receptor Activator Of Nuclear Factor Kappa B Ligand (RANKL) expression in osteoblasts (Ryu et al., 2006). S1P production is finely regulated through multiple mechanisms. Cathepsin K has been shown to inhibit S1P production by repressing SPHK1 kinase activity (Lotinun et al., 2013). Similarly, the thyroid hormone calcitonin, which binds the transmembrane calcitonin receptor (CTR) on the osteoclast membrane, acts as a negative regulator of SPNS2 expression likely through phospholipase C signaling thereby reducing S1P secretion (Keller et al., 2014). Thus, CTR-deficient mice exhibit higher S1P levels in bone, resulting in an increased bone formation rate (Keller et al., 2014).

Administration of an S1P analog able to act on four out of the five S1P receptors resulted in increased bone formation and mineralization in mice (Weske et al., 2018). However, increased OPG levels and reduced osteoclast numbers were observed in treated animals, leading to questioning if the positive effect is due to S1P anabolic activity or mostly to its autocrine inhibitory effect on osteoclasts (Weske et al., 2018; Sims and Martin, 2020). Further studies will help to clarify the primary role of S1P on bone metabolism in vivo.

Collagen triple helix repeat containing 1 (CTHRC1) is a highly conserved secreted glycoprotein that was first identified in the arterial wall in response to injury (Pyagay et al., 2005; LeClair and Lindner, 2007), where it acted as a regulator of TGF-β1 signaling during vascular remodeling (LeClair and Lindner, 2007). Later, it was found to be expressed in the cartilage growth plate during mouse development (Kimura et al., 2008). In adulthood, CTHRC1 is primarily found in bone, with minimal expression in the brain (Takeshita et al., 2013). CTHRC1 was shown to stimulate osteogenic differentiation and suppression of adipocytic differentiation of marrow stromal cells (Takeshita et al., 2013). The importance of CTHRC1 in promoting bone formation to preserve bone mass and trabecular structure was ascertained through conditional deletion in Ctsk positive cells and global deletion experiments which resulted in low bone mass characterized by decreased trabecular number and thickness in mice (Takeshita et al., 2013).

Interestingly, CTHRC1 expression has been demonstrated to strongly correlate with the activity of osteoclasts, as demonstrated by its increased expression in osteoclasts placed on dentin or hydroxyapatite, and reduced expression after alendronate treatment or aging (Takeshita et al., 2013). Its association with high bone turnover states suggests its potential as a biomarker or therapeutic target for the diagnosis and treatment of bone diseases such as osteoporosis. WNT-activated inhibitory factor 1 (WAIF1), encoded by the trophoblast glycoprotein (TPBG) gene, was identified as a receptor for CTHRC1 on stromal cells and osteoblasts (Matsuoka et al., 2018), and WAIF1 binding to CTHRC1 and Tyrosine-Protein Kinase Transmembrane Receptor ROR2 was shown to promote osteoblast differentiation through activation of the PKCδ–ERK pathway (Matsuoka et al., 2018; Figure 2). Additionally, osteoblast-specific deletion of WAIF1 resulted in reduced bone formation, similar to the effects observed with conditional CTHRC1 knockout in osteoclasts, confirming the dysregulation of the coupling mechanism mediated by both proteins (Matsuoka et al., 2018).

While the in vivo data unequivocally show the role of CTHRC1 as a promoter of osteoblast differentiation, its actual production by osteoclasts has recently become conflicting. While an earlier study showed Cthrc1 transcript expression in multinucleated osteoclasts on mouse trabecular bone, latest research has demonstrated that, in the same tissue, CTHCR1 protein does not colocalize with the osteoclast marker TRAP and is rather present in osteoblasts and osteocytes (Jin et al., 2017). More studies are required to clarify this discrepancy and demonstrate whether CTHRC1 truly acts as a coupling factor secreted by osteoclasts or signals within the osteoblast lineage.

C3a is a small peptide produced through the proteolytic cleavage of C3 during the initial phases of complement activation (Dunkelberger and Song, 2010) and is expressed by several cell types, such as immune cells (Lubbers et al., 2017), hepatocytes (Han and Zhang, 2021), but also osteoblasts and osteoclasts (Ignatius et al., 2011). C3a was identified in conditioned media of osteoclasts as a factor promoting osteoblast differentiation in vitro. Its role as a clastokine was further elucidated after observing reduced osteoblast mineralization following knockdown of C3 gene expression in osteoclasts and increased ALP activity following administration of a C3a receptor (C3aR) agonist in osteoblast cultures (Matsuoka et al., 2014). Moreover, increased levels of C3a were reported in ovariectomized mice, characterized by a high turnover state (Matsuoka et al., 2014). In this model, administration of a C3aR antagonist inhibited bone formation and exacerbated bone loss and trabecular architecture deterioration, providing evidence of C3a function in vivo (Matsuoka et al., 2014). The downstream signaling pathways that are activated through osteoclast-derived C3a interaction with C3aR on osteoblasts likely involve ERKs, but the precise mechanism remains to be determined (Matsuoka et al., 2014; Figure 2). Notably, C3 expression was observed to increase in osteoblasts treated with 1α,25-dihydroxyvitamin D3 (Matsuoka et al., 2014; Sato et al., 1991); however, C3a protein could not be detected in osteoblast conditioned medium (Sato et al., 1991). This suggests the presence of a specific processing system for C3a production present in osteoclasts but not in osteoblasts (Sato et al., 1991), which may ultimately influence its function depending on the cell source.

The WNT signaling pathway has great relevance in the skeletal field, as WNT proteins are well-known regulators of skeletal development and homeostasis (Zhong et al., 2014). They carry out their function through two pathways: the canonical WNT-β–catenin pathway and the noncanonical WNT pathway, that is further classified into two sub-pathways, the WNT–Ca²⁺ and the WNT–JNK pathways (Albrecht et al., 2021; Lojk and Marc, 2021).

Wingless-type MMTV integration site family, member 5 (WNT5A) secreted by osteoblasts was found to enhance osteoclastogenesis in vivo following RANKL stimulation (Maeda et al., 2012). Osteoblast-derived WNT5A was shown to interact with ROR2 located on the osteoclast surface, inducing noncanonical WNT signaling. This leads to the phosphorylation of JNK, followed by c-Jun-Sp1-mediated transactivation of the Tnfrsf11a gene, encoding the receptor RANK, which in turn results in increased RANK expression in osteoclast precursors (Maeda et al., 2012). Hence, the WNT5A–ROR2 axis promotes osteoclastogenesis, controlling osteoclast number, and bone resorption activity through coordinated signaling (Maeda et al., 2012). Additionally, WNT5A can promote osteoclastogenesis by abrogating the inhibitory signals of WNT16, but the mechanism is independent from ROR2 as WNT16 was demonstrated to not be able to bind the receptor (Kobayashi et al., 2015).

Due to the various roles of WNT5A, not only related to osteoblast–osteoclast communication (Gofflot et al., 1998), the hypothesis that WNT5A functionality could be dependent on the cell of origin and cell context was already postulated around 10 years ago (Zhong et al., 2014). A recent study highlighted the complexity of WNT5A mechanisms in preserving bone homeostasis. Starting from the already known ability of osteoblast-derived WNT5A to influence osteoclasts, the study was aimed at investigating the role of osteoclast-derived WNT5A. Conditional removal of WNT5A in osteoclasts resulted in decreased bone mass in vivo, which was not due to altered osteoclast number or activity, but due to decreased bone formation by osteoblasts (Roberts et al., 2020). Interestingly, osteoclast-derived WNT5A was shown to differ from osteoblast-derived WNT5A by the presence of post-translational modifications, specifically the phosphorylation of specific Serine residues (Roberts et al., 2020; Figure 2). These findings uncovered an unexpected clastokine role for WNT5A, which is post-translationally modified in a cell-type-specific manner to acquire its function (Roberts et al., 2020). Further studies are needed to define how osteoclast-derived WNT5A communicates with osteoblasts and its mechanism of action.

WNT10B is another member of the WNT ligand gene family known to specifically activate canonical WNT/β-catenin signaling (Wend et al., 2012). Pederson et al. showed that WNT10B along with S1P was also expressed in osteoclasts and was able to induce human MSC differentiation and mineralization in vitro (Pederson et al., 2008).

Recently, researchers have suggested that Cinacalcet, a calcimimetic compound, can improve bone mineralization, bone quantity, and quality in chronic kidney disease mice by increasing WNT10B secretion by osteoclasts (Zheng et al., 2019). Similarly, expression of WNT10B by osteoclasts was also stimulated by calcitonin (Figure 2), resulting in improved bone parameters and increased bone mineralization in ovariectomy-induced osteoporotic rats (Hsiao et al., 2020). These studies suggest that calcitonin may play a role in the coupling mechanism by modulating osteoblast mineralization through the controlled secretion of WNT10B and S1P.

The glycoprotein 130 (gp130)-binding cytokine LIF was already known to promote mitogenic activity in osteoblasts as early as 1997 (Cornish et al., 1997). However, its identification as a coupling factor produced by osteoclasts in response to TGF-β1 stimulation was only made recently (Ota et al., 2013b). LIF exerts its clastokine activity by downregulating sclerostin expression and upregulating WNT/β–catenin pathway components in osteoblasts to promote bone formation (Ota et al., 2013b; Figure 2). A recent study on bone biopsies from post-menopausal women revealed LIF to be highly expressed in osteoclasts compared to osteoblasts and to be suppressed by Denosumab treatment, confirming its role as a clastokine to be conserved and present during human bone remodeling (Weivoda et al., 2020).

Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines and was originally discovered as a factor inducing cardiac myocyte hypertrophy (Pennica et al., 1995). While its hypertrophic and cardioprotective effects have been the most extensively characterized, other effects of CT-1 on different tissues have also been reported (Peters et al., 1995; López-Yoldi et al., 2015). CT-1 is expressed in bone, specifically in osteoclasts but not osteoblasts or osteocytes (Sims and Walsh, 2010). Osteoclast-derived CT-1 was described to act as a clastokine to promote osteoblast mineralization in vitro and in vivo when administered over the calvariae of young mice (Walker et al., 2008). CT-1 knockout in young mice resulted in a significant reduction in trabecular bone volume, trabecular number, and osteoblast number, confirming its role in promoting bone formation, especially during early developmental stages (Walker et al., 2008). CT-1 also appears to regulate, likely through an autocrine mechanism, osteoclast number, size, and function since genetic deletion of CT-1 leads to an increased number of larger osteoclasts and impaired bone resorption (Walker et al., 2008). The mechanism by which CT-1 exerts its effects has been proposed to be related to the activation of CCAAT/enhancer-binding protein δ (C/EBPδ), which induces RUNX2-dependent osteocalcin transcription in osteoblasts (Walker et al., 2008; Figure 2). Increased levels of phosphorylated STAT3 and ERK were also detected after CT-1 administration to stromal cells, indicating their contribution to its clastokine activity (Walker et al., 2008). Similar to LIF, CT-1 is a gp130-binding cytokine. Both their stimulatory signals are mediated by the formation of ligand–receptor complexes with LIF receptor (LIFR) and gp130 heterodimers on the osteoblast membrane (Sims and Walsh, 2010). The gp130 pathway has important key roles in bone homeostasis by regulating the differentiation and activity of osteoblasts, osteoclasts, and chondrocytes (Johnson et al., 2014; Johnson et al., 2015; Liu et al., 2022). The ability of gp130 to mediate clastokine signals sheds new light on the multifaceted activity of this receptor, confirming its fundamental function in preserving bone balance.

Slit Guidance Ligand 3 (SLIT3) belongs to the SLIT family, a group of secreted proteins acting as molecular cues to control migration in several cell types (Geutskens et al., 2010; Zhang et al., 2009; Dou et al., 2018; Kramer et al., 2001; Wang et al., 1999). SLIT3 involvement in bone homeostasis was only recently acknowledged after its identification in purified conditioned media from mature osteoclasts which was able to stimulate migration of osteoblast lineage cells (Kim et al., 2012). This ability was also confirmed in vivo by increased bone marrow mobilization following injection of SLIT3 of GFP-labeled osteoblasts in the mouse tibia (Kim et al., 2018). Two independent groups showed that global knockout of SLIT3 in mice results in reduced skeletal size and a severely osteoporotic phenotype compared to their WT littermates (Kim et al., 2018; Xu et al., 2018). In the first study Slit3^−/− mice also displayed increased bone resorption parameters and osteoclast numbers (Kim et al., 2018), pointing out SLIT3 as an osteoprotective molecule capable of stimulating bone formation while simultaneously suppressing bone resorption. However, those findings were not recapitulated in the study from the second group (Takeshita et al., 2013; Li et al., 2020). Furthermore, while both groups used Ctsk:Cre to create a conditional knockout for SLIT3, only one of them was able to observe an osteoporotic phenotype associated with lack of SLIT3 in osteoclasts (Kim et al., 2018; Li et al., 2020). The different nature of the floxed mice used to carry out the studies could possibly explain the discrepancy (Kim et al., 2018; Xu et al., 2018; Li et al., 2020).

The mechanism by which SLIT3 exerts its function has also been elucidated. SLIT3 is expressed by mature osteoclasts following RANKL stimulation (Kim et al., 2018). After secretion, SLIT3 can bind to Roundabout Guidance Receptors ROBO1 and ROBO2 located on the osteoblast surface, and to ROBO1 and ROBO3 receptors on osteoclasts. In osteoblasts, the downstream SLIT3/ROBO signaling involves the formation of a multimolecular complex consisting of ROBO protein, Abelson (Abl) tyrosine kinase, adaptor protein Cables (Cdk5 and Abl enzyme substrate 1), N-cadherin, and β-catenin (Blockus and Chédotal, 2016; Rhee et al., 2007). Following Abl phosphorylation, N-cadherin-associated β-catenin is released, leading to the loss of N-cadherin-mediated cell adhesion (Kim et al., 2018; Rhee et al., 2007; Koohini et al., 2019), and to β-catenin translocation to the nucleus (Kim et al., 2018), ultimately resulting in increased osteoblast migration and proliferation (Kim et al., 2018; Figure 2). The autocrine signaling of SLIT3 in osteoclasts involves the recruitment of SLIT3–ROBO GTPase activating protein 2 (srGAP2) to the intracellular domain of ROBO1 receptor with consequent Rac1 GTPase inhibition, reduced NF-κB expression and reduced osteoclast differentiation (Shin et al., 2020). A negative feedback loop further regulates the pathway, as Rac1 promotes SLIT3 expression, ultimately leading to increased srGAP2 and Rac1 suppression (Shin et al., 2020; Figure 2).

A recent study from the first group again confirmed SLIT3 increasing expression during osteoclast differentiation and enhanced bone loss in the Slit3^−/− mouse model (Kim et al., 2023), but the authors did not address the ongoing controversy. Multiple pieces of evidence support the role of SLIT3 in the coupling between bone resorption and bone formation (Kim et al., 2018; Shin et al., 2020). A third independent report would likely help to overcome these inconsistencies and clarify SLIT3 relevance as an osteoclast-derived clastokine.

Some factors are currently mentioned in the literature as ‘putative clastokines’ as only limited data are currently available for these molecules, mostly restricted to in vitro studies. Therefore, further studies are required to prove their function as clastokines.

The new member of the albumin family, afamin, was first identified in osteoclast conditioned media (Kim et al., 2012). Recombinant afamin was shown to stimulate mouse calvarial osteoblast migration in a dose-dependent manner by inducing lamellipodia formation, suggesting a role as a chemoattractant (Kim et al., 2012). Further confirmation came from an in vivo migration experiment in which preosteoblasts, injected together with afamin in mouse tibia, mainly localized in the areas of bone formation (Kim et al., 2012). Afamin was shown to activate AKT signaling in vitro, identifying this pathway as a possible mediator of its chemotactic activity (Kim et al., 2012).

The chemokine CXCL16 is a transmembrane protein which is released from the cell membrane following cleavage by disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) (Abel et al., 2004). Soluble CXCL16 produced by macrophages is responsible for the recruitment of T cells to sustain inflammation in rheumatoid arthritis (van der Voort et al., 2005). A study demonstrated that, in a similar fashion, CXCL16 produced by osteoclasts following TGF-β1 stimulation is able to initiate MSC migration to the sites of bone resorption (Ota et al., 2013b), suggesting that this molecule may act as a clastokine during bone remodeling.

Bone morphogenetic proteins (BMPs) are a large family of growth factors that play critical roles in skeletal development and maintenance. Among the different types of BMPs present in bone, BMP2, BMP4, BMP6, and BMP7 have been shown to be able to induce bone formation in vivo (Katagiri and Watabe, 2016). Interestingly, they all can also be expressed by osteoclasts (Spector et al., 2001; Jensen et al., 2010). In particular, BMP6 was identified as an osteoclast-derived factor able to promote human MSC differentiation and mineralization in vitro. Furthermore, BMP6 was also reported to promote MSC migration in a wound healing assay (Pederson et al., 2008). No other studies have confirmed the relevance of BMP6 as a clastokine so far, therefore its function in bone homeostasis remains largely uncharacterized.

Several reports indicate platelet-derived growth factor-BB (PDGF-BB), one of the most potent known chemoattractants for human MSCs (Fiedler et al., 2004), as a functional candidate in the osteoclast-dependent regulation of bone formation. Earlier studies have shown that PDGF-BB can be released from its heparin and collagen matrix bound form during bone resorption (Ross et al., 1986; Sun et al., 2009). However, more recent research has demonstrated that PDGF-BB can also directly be secreted by osteoclasts. Interaction of PDGF-BB with PDGF-receptor β on the osteoblast surface induces the migration of osteoblasts and osteoblast precursors (Kreja et al., 2010), but the downstream cascade of signaling events is still unclear (Jaganathan et al., 2007; Kallin et al., 2004; Rivera et al., 2006). This was confirmed by a significantly reduced chemotactic response of osteoblasts and preosteoblastic cells to osteoclasts in which PDGF-BB expression was downregulated by siRNA (Kreja et al., 2010; Sanchez-Fernandez et al., 2008). One of these works claimed osteoclast chemotactic potency to be dependent on their level of differentiation (Sanchez-Fernandez et al., 2008), but it was demonstrated that the migration stimulatory effect on osteoblasts was not linked to osteoclast resorptive activity as conditioned media from non-resorbing, mononuclear osteoclast cultures were shown to be able to induce osteogenic differentiation (Kreja et al., 2010). This suggests that the ability of osteoclasts to secrete clastokines is not necessarily related to their resorptive state.

Despite the evident role on osteoblast migration, the effect of PDGF-BB on bone formation is still controversial. Some published evidence supports its inhibitory role on osteoblastogenesis in vitro (Kubota et al., 2002; O’Sullivan et al., 2007; Fierro et al., 2007), supporting the idea that PDGF-BB increases osteoblast proliferation at the expenses of differentiation. However, some older literature pointed out a positive effect of PDGF-BB on bone formation and bone healing in vivo, as its administration accelerated fracture healing in tibial osteotomies in rabbits and increased bone parameters in ovariectomized rats (Nash et al., 1994; Mitlak et al., 1996). Further studies are needed to clarify the mechanisms and effects by which PDGF-BB operates to maintain bone homeostasis in vivo. Conditional inactivation of PDGF-BB in osteoclasts or PDGF-β in osteoblasts, along with the administration of osteoclast-derived PDGF-BB in murine models, could represent strategies to address the physiological role of this factor.

Hepatocyte growth factor (HGF), expressed in both osteoblasts and osteoclasts, was postulated as a coupling factor for the first time in 1996. In this study, HGF produced by osteoclasts was found to increase the number of osteoclasts and, at the same time, to induce proliferation of osteoblasts in vitro (Grano et al., 1996). Researchers hypothesized that osteoclasts could act as coordinators of bone formation and bone resorption to maintain bone balance by secreting HGF acting through autocrine and paracrine mechanisms (Grano et al., 1996). HGF stimulates osteoblasts by binding to its canonical receptor c-Met on the osteoblast surface. The consequent activation of PI3K, AKT, and c-Src leads to enhanced binding of c-Jun to the AP-1 site and increased expression of osteopontin (OPN) (Chen et al., 2012).

The coupling of bone resorption to bone formation involves not only the secretion of factors at the remodeling site, but also the production of specific extracellular vesicles (EVs) by osteoclasts. EVs serve as important messengers in the bone microenvironment, delivering cytokines, microRNAs (miRNAs), and growth factors from one cell type to another (Liu et al., 2018). Unlike paracrine signaling, EVs provide a protective environment for their cargo, ensuring effective communication, and fine regulation of the crosstalk between bone cells (Liu et al., 2018).

miRNAs have emerged as important regulators of bone homeostasis, although whether they were secreted or shuttled through EVs remained uncertain for some time (Collino et al., 2010; Lian et al., 2012). A recent study identified 12 miRNAs inside osteoclast-derived EVs, among which miR-214-3p was found to be delivered to osteoblasts, acting as an intercellular messenger (Li et al., 2016). miR-214-3p targets Activating Transcription Factor 4 (ATF4), a transcription factor involved in osteoblast differentiation, thereby suppressing osteoblast differentiation and subsequent bone formation (Li et al., 2016; Wang et al., 2013). Previous work did also show miR-214-3p-mediated suppression of osteogenic differentiation of C2C12 myoblasts by targeting Osterix (Shi et al., 2013). The proposed mechanism for miR-214-3p delivery to osteoblasts involves the recognition of EFNA2, located on the vesicle membrane, by its receptor EPHA2 on osteoblasts, resulting in increased RhoA activity (Sun et al., 2016). Another miRNA, miR-324, present in osteoclast-derived EVs, was shown to be able to promote osteogenic differentiation in vitro and to induce bone formation in a calvaria defect model in vivo (Liang et al., 2021). miR-324 coupling activity is carried out by downregulation of the expression of ARHGAP1, a member of the RhoGAP family containing GTPase-activating proteins, stimulating RhoA/ROCK signaling, and ultimately enhancing osteoblast differentiation and mineralization (Liang et al., 2021). These data prove that miRNAs produced by osteoclasts can influence osteoblast behavior during bone remodeling, acting as intercellular communication tools to regulate bone homeostasis.

The established communication between osteoclasts and osteoblasts through the RANKL–RANK–OPG axis has been a hallmark of osteoblastic control of osteoclasts (Takegahara et al., 2022). However, recent research brought to light an unexpected role for this signaling pathway, revealing the existence of RANKL reverse signaling. This was initially observed through the use of RANKL-binding peptides which inhibit RANKL-induced osteoclastogenesis, but additionally resulted in increased bone formation in vivo (Takasaki et al., 1997; Aoki et al., 2006; Furuya et al., 2013; Sawa et al., 2018; Cheng et al., 2004; Kato et al., 2015), indicating the presence of a pathway where membrane-bound RANKL acts as a receptor to stimulate osteoblast differentiation. Deeper investigation into the putative ligand able to promote bone formation through RANKL identified this factor as the osteoclast transmembrane receptor RANK (Ikebuchi et al., 2018). Indeed, it was shown that maturing osteoclasts can secrete small EVs containing RANK, that activate the pathway (Ikebuchi et al., 2018). Vesicular RANK can bind to RANKL on the osteoblast surface and promote bone formation by activating the PI3K–Akt–mTORC1 pathway and triggering the production of RUNX2. The relevance of this mechanism was confirmed by the observation that suppression of RANKL reverse signaling leads to inefficient bone formation in vivo (Ikebuchi et al., 2018).

At the end of the resorptive phase, osteoclasts can undergo apoptosis and release apoptotic bodies whose function remain largely unknown. Curiously, a study revealed that apoptotic bodies from osteoclasts contained RANK and were able to stimulate RANKL reverse signaling, promoting mineralization by osteoblasts in vitro (Ma et al., 2021). This raises the question of why bisphosphonates, inducing osteoclast apoptosis, do not elicit a similar bone formation response when administered in vivo. Further studies are needed to elucidate this intriguing phenomenon within a physiological context.

The discovery that osteoclasts release multiple factors to promote bone formation and preserve bone homeostasis provides not only a deeper understanding of bone biology but also holds the potential for clinical applications in the diagnosis and therapy of bone diseases.

Therapies for metabolic bone diseases, such as osteoporosis, aim to increase bone mass by utilizing anti-resorptive or anabolic treatments to promote bone formation. Ideally, an effective treatment would target both mechanisms, considering the coupling between bone formation and bone resorption. However, currently approved drugs tend to focus on one singular mechanism, often destabilizing normal bone homeostasis in the process.

With over 50 years of clinical use (Bassett et al., 1969; Russell, 2011), bisphosphonates are the current treatment strategy to block bone resorption by disrupting osteoclast function and survival (Rogers et al., 2011; Reyes et al., 2016). While they effectively control bone resorption, slightly increase bone density, and reduce fracture risk, bisphosphonates also strongly disrupt the bone repair mechanism (Nyman et al., 2004). This can give rise to clinical complications such as osteonecrosis of the jaw and atypical femoral fractures (Carvalho et al., 2011; Koh et al., 2010; Khan et al., 2009). Similarly, PTH, the only approved anabolic drug for the treatment of osteoporosis together with the anti-sclerostin antibody Romosozumab (Lindsay et al., 2016), promotes bone formation, but also leads to increased bone resorption as a secondary effect (Silva et al., 2011).

In this scenario, clastokines present an appealing therapeutical target as they can simultaneously stimulate bone formation and reduce bone resorption. Proof-of-concept evidence and promising results from in vivo administration of clastokines such as SLIT3 and vesicular RANK in murine models suggest their potential in alleviating bone loss in metabolic bone diseases. Also, multiple reports indicate the possibility to use them as biomarkers to predict the susceptibility to fracture or disease.

Sclerostin, a natural inhibitor of the canonical WNT pathway and subsequently of bone formation, is a target for therapeutic intervention (Delgado-Calle et al., 2017). An anti-sclerostin antibody is currently FDA approved as a treatment for osteoporosis and rare genetic diseases such as osteogenesis imperfecta (Fabre et al., 2020; Aditya and Rattan, 2021; Marom et al., 2020), and the administration of PTH itself can reduce sclerostin levels (Keller and Kneissel, 2005). However, concerns have been raised about the possibility of serious adverse cardiovascular events following sclerostin inhibition (Pietrzyk et al., 2017; Bovijn et al., 2020; Kawaguchi, 2020), and anti-sclerostin antibodies are generally contraindicated in case of a history of myocardial infarction or stroke (Krupa et al., 2023). Interestingly, both CT-1 and LIF clastokines were reported to strongly inhibit expression of sclerostin by osteocytes (Walker et al., 2010). This could imply the possibility to use these coupling factors as therapies without the risk of adverse events associated with the use of anti-sclerostin antibodies (Figure 3). However, further studies are required to determine the applicability of this approach. Another intriguing finding is the increased secretion of LIF by osteoclasts during early abnormal bone remodeling in an unstable murine model of osteoarthritis. This observation opens the possibility of utilizing this factor as a biomarker or therapeutic target for the disease (Zhao et al., 2022; Figure 3).

Figure 3

Download asset Open asset

Human recombinant SLIT3 LRRD2, a truncated form of SLIT3 composed of 130 amino acids, was shown to stimulate osteoblast migration and proliferation by inducing the release of N-cadherin-associated β-catenin, similar to full-length SLIT3. Furthermore, LRRD2 was found to associate with ROBO1 and ROBO2 receptors in osteoblasts, and ROBO1 and ROBO3 receptors in osteoclasts, thus exerting the same signaling events as its full-length form. Interestingly, ovariectomized mice intravenously injected with LRRD2 demonstrated significantly improved bone mass and bone parameters (Kim et al., 2018). These findings are particularly significant as SLIT3 represents a very appealing potential therapy for metabolic bone diseases due to its osteoprotective nature, inhibiting bone resorption while stimulating bone formation. Furthermore, significant progress has been made in the potential use of SLIT3 as a biomarker. Elevated plasma levels of SLIT3 were found to correlate with higher bone mineral density at the lumbar spine and proximal femoral sites in a large cohort of postmenopausal women. This suggests that circulating SLIT3 could serve as a valuable biomarker for predicting bone health in humans (Kim et al., 2018; Figure 3).

Similar to SLIT3, RANKL is an intriguing pharmacological target for simultaneously stimulating bone formation and inhibiting bone resorption. Researchers identified a bifunctional antibody (αR-bif) capable of inhibiting RANKL forward signaling while activating RANKL reverse signaling. The peptide, administered in a murine model of postmenopausal osteoporosis, partially rescued the phenotype by suppressing osteoclast differentiation and simultaneously stimulating bone formation (Furuya et al., 2013). The humanized monoclonal antibody Denosumab, blocking RANKL and exerting potent antiresorptive activity, is currently used as a treatment for osteoporosis (Cummings et al., 2009; McClung et al., 2006; Lewiecki et al., 2007). Contrarily to bisphosphonates, long-term treatment with Denosumab has shown to sustain a continued increase in bone mineral density, pointing out a unique mechanism of action of the drug (Törring, 2015). Recent hypotheses suggest that Denosumab may trigger RANKL reverse signaling thus stimulating an anabolic response in osteoblasts (Portal-Núñez et al., 2017). If validated, this would not only demonstrate the relevance of the signaling pathway in a human physiological context but also support the clinical applicability of targeting this coupling mechanism (Figure 3).

The observation that not all clastokines are necessarily expressed by mature osteoclasts indicates that osteoclasts can release coupling factors to promote bone formation while not actively resorbing bone. Studies conducted on osteopetrotic animals confirmed that induction of bone formation by osteoclasts can occur independently of their resorptive ability (Karsdal et al., 2007; Segovia-Silvestre et al., 2009; Del Fattore et al., 2006). This concept carries significant clinical implications since targeting osteoclastic bone resorption, rather than osteoclast differentiation, could be pursued without affecting bone formation. In this context, the use of cathepsin K inhibitors, in contrast to antiresorptive agents, represented a promising approach as they reduce osteoclast function while maintaining or even increasing the number of osteoclasts that retain their ability to secrete coupling factors and communicate with osteoblasts to promote their function and activity (Drake et al., 2017). Interestingly, cathepsin K inhibition has a stimulatory effect on S1P clastokine production (Lotinun et al., 2013). However, since cathepsin K function is not limited to bone, but is also present in brain, cardiovascular system, and lungs (Dai et al., 2020), its inhibition can have detrimental side effects on these tissues (Drake et al., 2017). This raised concerns limiting the development of new inhibitors and withdrawal of the cathepsin K inhibitor Odanacatib from a phase III clinical trial due to an increased risk of cerebrovascular accidents (Chen et al., 2023). Nevertheless, targeting bone resorption without compromising osteoclast number remains an alternative strategy to bisphosphonates that can be explored to take advantage of the coupling effect in the context of bone diseases.

Intriguingly, recent research showed titanium nanotubular surfaces with the ability to modulate macrophage and osteoclast secretory profiles toward the production of pro-healing cytokines and pro-osteogenic clastokines such as BMP6, CTHRC1, HGF, SLIT3, and WNT10B, respectively (He et al., 2022). This significant discovery paves the way for the potential application of titanium osteoimplants able to accelerate bone regeneration through clastokine production and represent a proof-of-concept for their future translation into the clinic (Figure 3).

Taken together, multiple pieces of evidence show clastokine potential for the treatment of bone diseases. The application of new refined technologies will likely help to decipher the specific mechanisms governing clastokine anabolic activity and understand how to translate such information into therapeutic solutions with clinical applicability.

Osteoclasts are not inert spectators of the BMU and work in concert with osteoblasts to preserve bone homeostasis. During bone remodeling, osteoclasts play a key role in the switch from bone resorption to bone formation (Figure 4). This can be achieved by their active release of factors from the extracellular matrix, engaging in direct cell–cell contact and, most intriguingly, by secretion of coupling factors known as clastokines that signal through osteoblast receptors.

Figure 4

Download asset Open asset

The discovery of clastokines, although challenging, has sparked significant interest in the field. Continuous advancements in technology have facilitated the identification of new potential clastokines (Weivoda et al., 2020), while further research has revealed the molecular mechanisms of already known clastokines during human bone remodeling (Borggaard et al., 2022), emphasizing their conserved role in maintaining bone homeostasis and evidencing how large-scale genetic screening combined with bioinformatic prediction, and exploration of the osteoclast secretome are powerful approaches to efficiently identify such factors in humans.

Despite the efforts made in unraveling the intriguing world of clastokines, a lot of open questions remain about the mechanisms and pathways governing clastokine function and therefore there is a compelling need for more comprehensive investigation to provide a deeper understanding of clastokine function.

Osteoclasts, mostly in the mature stage but also independently of their differentiation, can positively stimulate osteoblast activity. The recent discovery of recycling osteomorphs, a new osteoclast type involved in the regulation of bone remodeling, raises an intriguing question: could there be a distinct osteoclast subtype with the specialized capacity to secrete clastokines and orchestrate osteoblast differentiation? And if so, how is it distinct from other types of osteoclasts? This interesting possibility requires further exploration and use of recently developed single-cell technologies could hold the key to answering this question.

The in vitro study of osteoclast-derived clastokines has a lot of space for technological improvement as the way that research has been carried out has not changed much with time. For instance, the use of conditioned media from osteoclasts to induce osteoblast differentiation could be replaced by direct co-cultures, which could not only address the presence of secreted factors, but also identify mechanisms of direct cell–cell communication, which are yet poorly explored and understood. Recent work using co-cultures of cells expressing Ephrin A1 and its receptor EPHA2, respectively, has nicely shown the trafficking of Ephrins through live cell imaging (Valenzuela and Perez, 2020). A similar approach could be applied to study clastokine secretion and trafficking between osteoclasts and osteoblasts.

There is also a strong need for in vivo validation of in vitro data. Many murine models used for the study of clastokine function are global knockouts, demanding the need to study osteoclast-specific knockouts to show the contribution of osteoclast-secreted factors to the observed phenotype. Challenges arise also from the fact that the most widely used osteoclast driver, Ctsk-Cre, has recently been identified to be active in various other skeletal cell types including osteoblasts, making it difficult to specifically associate the observed phenotype to the osteoclast per se and complicating the interpretation of the results (Debnath et al., 2018; Ruiz et al., 2016; Chai et al., 2023). In this light, the use of LysM-Cre, targeting the myeloid lineage, offers an alternative strategy to conditionally delete gene function in myeloid cells including osteoclasts. The combinatorial use of Cre and Dre recombinases would also represent a more refined way to achieve cell specific and efficient genetic targeting for the study of osteoclast function (Wang et al., 2022), fundamental in the field of clastokine research. The non-tissue-specific expression of some of the transgenes can be traced back to the specific promoter fragment used or local effects at the integration site of the transgene (Michalski and Williams, 2023). New genome editing techniques based on the Clustered Regularly Interspaced Palindromic Repeat CRISPR/Cas system open up the possibilities to efficiently modify the endogenous gene locus, circumventing some of the previously mentioned limitations of other transgenesis strategies (Gurumurthy et al., 2019; Ohtsuka and Sato, 2019).

While we have a better-defined picture of how clastokines work in a physiological context, our knowledge regarding their role in bone diseases remains limited. It is widely accepted that metabolic bone diseases are associated with a disruption in osteoblast to osteoclast communication. However, if this is also true for osteoclast to osteoblast communication remains an open question. Knowledge about how clastokine secretion by osteoclasts is affected in a pathological context, would allow the use of clastokines as biomarkers of disease states and provide opportunities to target their function to develop specific therapies.

Unquestionably, a growing body of evidence supports the therapeutic potential of clastokines for the treatment of bone diseases. The tight coupling between bone resorption and bone formation still represents nowadays an obstacle to the promotion of bone anabolism by singularly targeting either mechanism. Clastokines, owing to their osteoprotective role and their ability to couple bone formation and resorption toward bone anabolism, hold promise as therapeutic agents to overcome this limitation. The osteoprotective functionalities of S1P and SLIT3, the latter already demonstrated to act as an anabolic drug in vivo, represent novelties with great clinical potential. The discovery of RANKL reverse signaling mediated by osteoclast-derived vesicular RANK represents an interesting pharmaceutical target to bidirectionally stimulate osteoblasts and inhibit osteoclast differentiation and will be worth further attention. Notably, the paracrine signaling of osteoclasts is independent of their resorptive state, allowing for the selective targeting of bone resorption without disrupting osteoclast differentiation and consequently the coupling mechanism, thus offering another possible strategy for targeted therapies.

In conclusion, this review highlights the pivotal role of osteoclasts in orchestrating the dynamic interplay between bone resorption and formation. Significant steps forward have been made in identifying new clastokines and their anabolic effect over the past decades. The upcoming years are expected to bring further advancements, providing deeper insights into the mechanisms that these molecules adopt to preserve bone homeostasis. It is anticipated that, with the application of innovative technologies and strategies, the expanding field of clastokines and coupling factors will eventually translate into new clinical applications for the treatment of metabolic bone diseases.

1. 1. Abel S
   2. Hundhausen C
   3. Mentlein R
   4. Schulte A
   5. Berkhout TA
   6. Broadway N
   7. Hartmann D
   8. Sedlacek R
   9. Dietrich S
   10. Muetze B
   11. Schuster B
   12. Kallen KJ
   13. Saftig P
   14. Rose-John S
   15. Ludwig A

   (2004) The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10

   Journal of Immunology 172:6362–6372.

   https://doi.org/10.4049/jimmunol.172.10.6362

   • PubMed
   • Google Scholar
2. 1. Aditya S
   2. Rattan A

   (2021) Sclerostin inhibition: a novel target for the treatment of postmenopausal osteoporosis

   Journal of Mid-Life Health 12:267–275.

   https://doi.org/10.4103/jmh.JMH_106_20

   • PubMed
   • Google Scholar
3. 1. Albrecht LV
   2. Tejeda-Muñoz N
   3. De Robertis EM

   (2021) Cell biology of canonical wnt signaling

   Annual Review of Cell and Developmental Biology 37:369–389.

   https://doi.org/10.1146/annurev-cellbio-120319-023657

   • PubMed
   • Google Scholar
4. 1. Aoki K
   2. Saito H
   3. Itzstein C
   4. Ishiguro M
   5. Shibata T
   6. Blanque R
   7. Mian AH
   8. Takahashi M
   9. Suzuki Y
   10. Yoshimatsu M
   11. Yamaguchi A
   12. Deprez P
   13. Mollat P
   14. Murali R
   15. Ohya K
   16. Horne WC
   17. Baron R

   (2006) A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss

   The Journal of Clinical Investigation 116:1525–1534.

   https://doi.org/10.1172/JCI22513

   • PubMed
   • Google Scholar
5. 1. Arana-Chavez VE
   2. Bradaschia-Correa V

   (2009) Clastic cells: mineralized tissue resorption in health and disease

   The International Journal of Biochemistry & Cell Biology 41:446–450.

   https://doi.org/10.1016/j.biocel.2008.09.007

   • PubMed
   • Google Scholar
6. 1. Asagiri M
   2. Takayanagi H

   (2007) The molecular understanding of osteoclast differentiation

   Bone 40:251–264.

   https://doi.org/10.1016/j.bone.2006.09.023

   • PubMed
   • Google Scholar
7. 1. Bassett CA
   2. Donath A
   3. Macagno F
   4. Preisig R
   5. Fleisch H
   6. Francis MD

   (1969) Diphosphonates in the treatment of myositis ossificans

   Lancet 2:845.

   https://doi.org/10.1016/s0140-6736(69)92293-4

   • PubMed
   • Google Scholar
8. 1. Blockus H
   2. Chédotal A

   (2016) Slit-robo signaling

   Development 143:3037–3044.

   https://doi.org/10.1242/dev.132829

   • PubMed
   • Google Scholar
9. 1. Borggaard XG
   2. Nielsen MH
   3. Delaisse JM
   4. Andreasen CM
   5. Andersen TL

   (2022) Spatial organization of osteoclastic coupling factors and their receptors at human bone remodeling sites

   Frontiers in Molecular Biosciences 9:896841.

   https://doi.org/10.3389/fmolb.2022.896841

   • PubMed
   • Google Scholar
10. 1. Bovijn J
    2. Krebs K
    3. Chen CY
    4. Boxall R
    5. Censin JC
    6. Ferreira T
    7. Pulit SL
    8. Glastonbury CA
    9. Laber S
    10. Millwood IY
    11. Lin K
    12. Li L
    13. Chen Z
    14. Milani L
    15. Smith GD
    16. Walters RG
    17. Mägi R
    18. Neale BM
    19. Lindgren CM
    20. Holmes MV

    (2020) Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics

    Science Translational Medicine 12:eaay6570.

    https://doi.org/10.1126/scitranslmed.aay6570

    • PubMed
    • Google Scholar
11. 1. Boyce BF

    (2013) Advances in the regulation of osteoclasts and osteoclast functions

    Journal of Dental Research 92:860–867.

    https://doi.org/10.1177/0022034513500306

    • PubMed
    • Google Scholar
12. 1. Cappariello A
    2. Maurizi A
    3. Veeriah V
    4. Teti A

    (2014) The great beauty of the osteoclast

    Archives of Biochemistry and Biophysics 558:70–78.

    https://doi.org/10.1016/j.abb.2014.06.017

    • PubMed
    • Google Scholar
13. 1. Capulli M
    2. Paone R
    3. Rucci N

    (2014) Osteoblast and osteocyte: games without frontiers

    Archives of Biochemistry and Biophysics 561:3–12.

    https://doi.org/10.1016/j.abb.2014.05.003

    • PubMed
    • Google Scholar
14. 1. Carvalho NNC
    2. Voss LA
    3. Almeida MOP
    4. Salgado CL
    5. Bandeira F

    (2011) Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide

    The Journal of Clinical Endocrinology and Metabolism 96:2675–2680.

    https://doi.org/10.1210/jc.2011-0593

    • PubMed
    • Google Scholar
15. 1. Chai W
    2. Hao W
    3. Liu J
    4. Han Z
    5. Chang S
    6. Cheng L
    7. Sun M
    8. Yan G
    9. Liu Z
    10. Liu Y
    11. Zhang G
    12. Xing L
    13. Chen H
    14. Liu P

    (2023) Visualizing cathepsin k-cre expression at the single-cell level with gfp reporters

    JBMR Plus 7:e10706.

    https://doi.org/10.1002/jbm4.10706

    • PubMed
    • Google Scholar
16. 1. Chen HT
    2. Tsou HK
    3. Chang CH
    4. Tang CH

    (2012) Hepatocyte growth factor increases osteopontin expression in human osteoblasts through PI3K, Akt, c-Src, and AP-1 signaling pathway

    PLOS ONE 7:e38378.

    https://doi.org/10.1371/journal.pone.0038378

    • PubMed
    • Google Scholar
17. 1. Chen X
    2. Wang Z
    3. Duan N
    4. Zhu G
    5. Schwarz EM
    6. Xie C

    (2018) Osteoblast-osteoclast interactions

    Connective Tissue Research 59:99–107.

    https://doi.org/10.1080/03008207.2017.1290085

    • PubMed
    • Google Scholar
18. 1. Chen R
    2. Chen C
    3. Geng B
    4. Yang C
    5. Xiao H
    6. Yang F
    7. Wang H
    8. Xia Y

    (2023) Efficacy and safety of odanacatib for osteoporosis treatment: a systematic review and meta-analysis

    Archives of Osteoporosis 18:67.

    https://doi.org/10.1007/s11657-023-01261-7

    • PubMed
    • Google Scholar
19. 1. Cheng X
    2. Kinosaki M
    3. Takami M
    4. Choi Y
    5. Zhang H
    6. Murali R

    (2004) Disabling of receptor activator of nuclear factor-kappaB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo

    The Journal of Biological Chemistry 279:8269–8277.

    https://doi.org/10.1074/jbc.M309690200

    • PubMed
    • Google Scholar
20. 1. Chung DJ
    2. Castro CHM
    3. Watkins M
    4. Stains JP
    5. Chung MY
    6. Szejnfeld VL
    7. Willecke K
    8. Theis M
    9. Civitelli R

    (2006) Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43

    Journal of Cell Science 119:4187–4198.

    https://doi.org/10.1242/jcs.03162

    • PubMed
    • Google Scholar
21. 1. Collino F
    2. Deregibus MC
    3. Bruno S
    4. Sterpone L
    5. Aghemo G
    6. Viltono L
    7. Tetta C
    8. Camussi G

    (2010) Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs

    PLOS ONE 5:e11803.

    https://doi.org/10.1371/journal.pone.0011803

    • PubMed
    • Google Scholar
22. 1. Compton JT
    2. Lee FY

    (2014) A review of osteocyte function and the emerging importance of sclerostin

    The Journal of Bone and Joint Surgery. American Volume 96:1659–1668.

    https://doi.org/10.2106/JBJS.M.01096

    • PubMed
    • Google Scholar
23. 1. Cornish J
    2. Callon KE
    3. Edgar SG
    4. Reid IR

    (1997) Leukemia inhibitory factor is mitogenic to osteoblasts

    Bone 21:243–247.

    https://doi.org/10.1016/s8756-3282(97)00144-0

    • PubMed
    • Google Scholar
24. 1. Crane JL
    2. Cao X

    (2014) Function of matrix IGF-1 in coupling bone resorption and formation

    Journal of Molecular Medicine 92:107–115.

    https://doi.org/10.1007/s00109-013-1084-3

    • PubMed
    • Google Scholar
25. 1. Crockett JC
    2. Rogers MJ
    3. Coxon FP
    4. Hocking LJ
    5. Helfrich MH

    (2011) Bone remodelling at a glance

    Journal of Cell Science 124:991–998.

    https://doi.org/10.1242/jcs.063032

    • PubMed
    • Google Scholar
26. 1. Cummings SR
    2. San Martin J
    3. McClung MR
    4. Siris ES
    5. Eastell R
    6. Reid IR
    7. Delmas P
    8. Zoog HB
    9. Austin M
    10. Wang A
    11. Kutilek S
    12. Adami S
    13. Zanchetta J
    14. Libanati C
    15. Siddhanti S
    16. Christiansen C
    17. FREEDOM Trial

    (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis

    The New England Journal of Medicine 361:756–765.

    https://doi.org/10.1056/NEJMoa0809493

    • PubMed
    • Google Scholar
27. 1. Dacquin R
    2. Domenget C
    3. Kumanogoh A
    4. Kikutani H
    5. Jurdic P
    6. Machuca-Gayet I

    (2011) Control of bone resorption by semaphorin 4D is dependent on ovarian function

    PLOS ONE 6:e26627.

    https://doi.org/10.1371/journal.pone.0026627

    • PubMed
    • Google Scholar
28. 1. Dai R
    2. Wu Z
    3. Chu HY
    4. Lu J
    5. Lyu A
    6. Liu J
    7. Zhang G

    (2020) Cathepsin k: the action in and beyond bone

    Frontiers in Cell and Developmental Biology 8:433.

    https://doi.org/10.3389/fcell.2020.00433

    • PubMed
    • Google Scholar
29. 1. Dallas SL
    2. Rosser JL
    3. Mundy GR
    4. Bonewald LF

    (2002) Proteolysis of latent transforming growth factor-beta (TGF-beta )-binding protein-1 by osteoclasts: a cellular mechanism for release of TGF-beta from bone matrix

    The Journal of Biological Chemistry 277:21352–21360.

    https://doi.org/10.1074/jbc.M111663200

    • PubMed
    • Google Scholar
30. 1. Debnath S
    2. Yallowitz AR
    3. McCormick J
    4. Lalani S
    5. Zhang T
    6. Xu R
    7. Li N
    8. Liu Y
    9. Yang YS
    10. Eiseman M
    11. Shim JH
    12. Hameed M
    13. Healey JH
    14. Bostrom MP
    15. Landau DA
    16. Greenblatt MB

    (2018) Discovery of a periosteal stem cell mediating intramembranous bone formation

    Nature 562:133–139.

    https://doi.org/10.1038/s41586-018-0554-8

    • PubMed
    • Google Scholar
31. 1. Del Fattore A
    2. Peruzzi B
    3. Rucci N
    4. Recchia I
    5. Cappariello A
    6. Longo M
    7. Fortunati D
    8. Ballanti P
    9. Iacobini M
    10. Luciani M
    11. Devito R
    12. Pinto R
    13. Caniglia M
    14. Lanino E
    15. Messina C
    16. Cesaro S
    17. Letizia C
    18. Bianchini G
    19. Fryssira H
    20. Grabowski P
    21. Shaw N
    22. Bishop N
    23. Hughes D
    24. Kapur RP
    25. Datta HK
    26. Taranta A
    27. Fornari R
    28. Migliaccio S
    29. Teti A

    (2006) Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment

    Journal of Medical Genetics 43:315–325.

    https://doi.org/10.1136/jmg.2005.036673

    • PubMed
    • Google Scholar
32. 1. Delgado-Calle J
    2. Sato AY
    3. Bellido T

    (2017) Role and mechanism of action of sclerostin in bone

    Bone 96:29–37.

    https://doi.org/10.1016/j.bone.2016.10.007

    • PubMed
    • Google Scholar
33. 1. Dou C
    2. Wang H
    3. Zhou G
    4. Zhu H
    5. Wen H
    6. Xu S

    (2018)

    Slit3 regulates migration of endothelial progenitor cells by activation of the rhoA/Rho kinase pathway

    International Journal of Clinical and Experimental Pathology 11:3398–3404.

    • PubMed
    • Google Scholar
34. 1. Downey PA
    2. Siegel MI

    (2006) Bone biology and the clinical implications for osteoporosis

    Physical Therapy 86:77–91.

    https://doi.org/10.1093/ptj/86.1.77

    • PubMed
    • Google Scholar
35. 1. Drake MT
    2. Clarke BL
    3. Oursler MJ
    4. Khosla S

    (2017) Cathepsin k inhibitors for osteoporosis: Biology

    Potential Clinical Utility, and Lessons Learned. Endocr Rev 38:325–350.

    https://doi.org/10.1210/er.2015-1114

    • Google Scholar
36. 1. Drissi H
    2. Sanjay A

    (2016) The multifaceted osteoclast; far and beyond bone resorption

    Journal of Cellular Biochemistry 117:1753–1756.

    https://doi.org/10.1002/jcb.25560

    • PubMed
    • Google Scholar
37. 1. Dunkelberger JR
    2. Song WC

    (2010) Complement and its role in innate and adaptive immune responses

    Cell Research 20:34–50.

    https://doi.org/10.1038/cr.2009.139

    • PubMed
    • Google Scholar
38. 1. Engler AJ
    2. Sen S
    3. Sweeney HL
    4. Discher DE

    (2006) Matrix elasticity directs stem cell lineage specification

    Cell 126:677–689.

    https://doi.org/10.1016/j.cell.2006.06.044

    • PubMed
    • Google Scholar
39. 1. Etich J
    2. Leßmeier L
    3. Rehberg M
    4. Sill H
    5. Zaucke F
    6. Netzer C
    7. Semler O

    (2020) Osteogenesis imperfecta-pathophysiology and therapeutic options

    Molecular and Cellular Pediatrics 7:9.

    https://doi.org/10.1186/s40348-020-00101-9

    • PubMed
    • Google Scholar
40. 1. Fabre S
    2. Funck-Brentano T
    3. Cohen-Solal M

    (2020) Anti-sclerostin antibodies in osteoporosis and other bone diseases

    Journal of Clinical Medicine 9:3439.

    https://doi.org/10.3390/jcm9113439

    • PubMed
    • Google Scholar
41. 1. Farley JR
    2. Tarbaux N
    3. Murphy LA
    4. Masuda T
    5. Baylink DJ

    (1987) In vitro evidence that bone formation may be coupled to resorption by release of mitogen(s) from resorbing bone

    Metabolism 36:314–321.

    https://doi.org/10.1016/0026-0495(87)90200-9

    • PubMed
    • Google Scholar
42. 1. Fiedler J
    2. Etzel N
    3. Brenner RE

    (2004) To go or not to go: migration of human mesenchymal progenitor cells stimulated by isoforms of PDGF

    Journal of Cellular Biochemistry 93:990–998.

    https://doi.org/10.1002/jcb.20219

    • PubMed
    • Google Scholar
43. 1. Fierro F
    2. Illmer T
    3. Jing D
    4. Schleyer E
    5. Ehninger G
    6. Boxberger S
    7. Bornhäuser M

    (2007) Inhibition of platelet-derived growth factor receptorbeta by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro

    Cell Proliferation 40:355–366.

    https://doi.org/10.1111/j.1365-2184.2007.00438.x

    • PubMed
    • Google Scholar
44. 1. Florencio-Silva R
    2. Sasso da GS
    3. Sasso-Cerri E
    4. Simões MJ
    5. Cerri PS

    (2015) Biology of bone tissue: Structure, function, and factors that influence bone cells

    BioMed Research International 2015:421746.

    https://doi.org/10.1155/2015/421746

    • PubMed
    • Google Scholar
45. 1. Furuya Y
    2. Inagaki A
    3. Khan M
    4. Mori K
    5. Penninger JM
    6. Nakamura M
    7. Udagawa N
    8. Aoki K
    9. Ohya K
    10. Uchida K
    11. Yasuda H

    (2013) Stimulation of bone formation in cortical bone of mice treated with a receptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity

    The Journal of Biological Chemistry 288:5562–5571.

    https://doi.org/10.1074/jbc.M112.426080

    • PubMed
    • Google Scholar
46. 1. Furuya M
    2. Kikuta J
    3. Fujimori S
    4. Seno S
    5. Maeda H
    6. Shirazaki M
    7. Uenaka M
    8. Mizuno H
    9. Iwamoto Y
    10. Morimoto A
    11. Hashimoto K
    12. Ito T
    13. Isogai Y
    14. Kashii M
    15. Kaito T
    16. Ohba S
    17. Chung U-I
    18. Lichtler AC
    19. Kikuchi K
    20. Matsuda H
    21. Yoshikawa H
    22. Ishii M

    (2018) Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo

    Nature Communications 9:300.

    https://doi.org/10.1038/s41467-017-02541-w

    • PubMed
    • Google Scholar
47. 1. Ge G
    2. Greenspan DS

    (2006) BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein

    The Journal of Cell Biology 175:111–120.

    https://doi.org/10.1083/jcb.200606058

    • PubMed
    • Google Scholar
48. 1. Geutskens SB
    2. Hordijk PL
    3. van Hennik PB

    (2010) The chemorepellent Slit3 promotes monocyte migration

    Journal of Immunology 185:7691–7698.

    https://doi.org/10.4049/jimmunol.0903898

    • PubMed
    • Google Scholar
49. 1. Gofflot F
    2. Hall M
    3. Morriss-Kay GM

    (1998)

    Genetic patterning of the posterior neuropore region of curly tail mouse embryos: deficiency of Wnt5a expression

    The International Journal of Developmental Biology 42:637–644.

    • PubMed
    • Google Scholar
50. 1. Grano M
    2. Galimi F
    3. Zambonin G
    4. Colucci S
    5. Cottone E
    6. Zallone AZ
    7. Comoglio PM

    (1996) Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro

    PNAS 93:7644–7648.

    https://doi.org/10.1073/pnas.93.15.7644

    • PubMed
    • Google Scholar
51. 1. Gurumurthy CB
    2. Sato M
    3. Nakamura A
    4. Inui M
    5. Kawano N
    6. Islam MA
    7. Ogiwara S
    8. Takabayashi S
    9. Matsuyama M
    10. Nakagawa S
    11. Miura H
    12. Ohtsuka M

    (2019) Creation of CRISPR-based germline-genome-engineered mice without ex vivo handling of zygotes by i-GONAD

    Nature Protocols 14:2452–2482.

    https://doi.org/10.1038/s41596-019-0187-x

    • PubMed
    • Google Scholar
52. 1. Han J
    2. Zhang X

    (2021) Complement component c3: a novel biomarker participating in the pathogenesis of non-alcoholic fatty liver disease

    Frontiers in Medicine 8:653293.

    https://doi.org/10.3389/fmed.2021.653293

    • PubMed
    • Google Scholar
53. 1. Hattner R
    2. Epker BN
    3. Frost HM

    (1965) Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling

    Nature 206:489–490.

    https://doi.org/10.1038/206489a0

    • PubMed
    • Google Scholar
54. 1. He Y
    2. Li Z
    3. Ding X
    4. Xu B
    5. Wang J
    6. Li Y
    7. Chen F
    8. Meng F
    9. Song W
    10. Zhang Y

    (2022) Nanoporous titanium implant surface promotes osteogenesis by suppressing osteoclastogenesis via integrin β1/FAKpY397/MAPK pathway

    Bioactive Materials 8:109–123.

    https://doi.org/10.1016/j.bioactmat.2021.06.033

    • PubMed
    • Google Scholar
55. 1. Hsiao CY
    2. Chen TH
    3. Chu TH
    4. Ting YN
    5. Tsai PJ
    6. Shyu JF

    (2020) Calcitonin induces bone formation by increasing expression of wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats

    Frontiers in Endocrinology 11:613.

    https://doi.org/10.3389/fendo.2020.00613

    • PubMed
    • Google Scholar
56. 1. Ignatius A
    2. Schoengraf P
    3. Kreja L
    4. Liedert A
    5. Recknagel S
    6. Kandert S
    7. Brenner RE
    8. Schneider M
    9. Lambris JD
    10. Huber-Lang M

    (2011) Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1β

    Journal of Cellular Biochemistry 112:2594–2605.

    https://doi.org/10.1002/jcb.23186

    • PubMed
    • Google Scholar
57. 1. Ikebuchi Y
    2. Aoki S
    3. Honma M
    4. Hayashi M
    5. Sugamori Y
    6. Khan M
    7. Kariya Y
    8. Kato G
    9. Tabata Y
    10. Penninger JM
    11. Udagawa N
    12. Aoki K
    13. Suzuki H

    (2018) Coupling of bone resorption and formation by RANKL reverse signalling

    Nature 561:195–200.

    https://doi.org/10.1038/s41586-018-0482-7

    • PubMed
    • Google Scholar
58. 1. Ilvesaro J
    2. Väänänen K
    3. Tuukkanen J

    (2000) Bone-resorbing osteoclasts contain gap-junctional connexin-43

    Journal of Bone and Mineral Research 15:919–926.

    https://doi.org/10.1359/jbmr.2000.15.5.919

    • PubMed
    • Google Scholar
59. 1. Ishii M
    2. Egen JG
    3. Klauschen F
    4. Meier-Schellersheim M
    5. Saeki Y
    6. Vacher J
    7. Proia RL
    8. Germain RN

    (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis

    Nature 458:524–528.

    https://doi.org/10.1038/nature07713

    • PubMed
    • Google Scholar
60. 1. Jaganathan BG
    2. Ruester B
    3. Dressel L
    4. Stein S
    5. Grez M
    6. Seifried E
    7. Henschler R

    (2007) Rho inhibition induces migration of mesenchymal stromal cells

    Stem Cells 25:1966–1974.

    https://doi.org/10.1634/stemcells.2007-0167

    • PubMed
    • Google Scholar
61. 1. Janssens K
    2. ten Dijke P
    3. Janssens S
    4. Van Hul W

    (2005) Transforming growth factor-beta1 to the bone

    Endocrine Reviews 26:743–774.

    https://doi.org/10.1210/er.2004-0001

    • PubMed
    • Google Scholar
62. 1. Jensen ED
    2. Pham L
    3. Billington CJ
    4. Espe K
    5. Carlson AE
    6. Westendorf JJ
    7. Petryk A
    8. Gopalakrishnan R
    9. Mansky K

    (2010) Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors

    Journal of Cellular Biochemistry 109:672.

    https://doi.org/10.1002/jcb.22462

    • PubMed
    • Google Scholar
63. 1. Jilka RL
    2. Weinstein RS
    3. Bellido T
    4. Parfitt AM
    5. Manolagas SC

    (1998) Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines

    Journal of Bone and Mineral Research 13:793–802.

    https://doi.org/10.1359/jbmr.1998.13.5.793

    • PubMed
    • Google Scholar
64. 1. Jin YR
    2. Stohn JP
    3. Wang Q
    4. Nagano K
    5. Baron R
    6. Bouxsein ML
    7. Rosen CJ
    8. Adarichev VA
    9. Lindner V

    (2017) Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

    Bone 97:153–167.

    https://doi.org/10.1016/j.bone.2017.01.022

    • PubMed
    • Google Scholar
65. 1. Johnson RW
    2. Brennan HJ
    3. Vrahnas C
    4. Poulton IJ
    5. McGregor NE
    6. Standal T
    7. Walker EC
    8. Koh TT
    9. Nguyen H
    10. Walsh NC
    11. Forwood MR
    12. Martin TJ
    13. Sims NA

    (2014) The primary function of gp130 signaling in osteoblasts is to maintain bone formation and strength, rather than promote osteoclast formation

    Journal of Bone and Mineral Research 29:1492–1505.

    https://doi.org/10.1002/jbmr.2159

    • PubMed
    • Google Scholar
66. 1. Johnson RW
    2. McGregor NE
    3. Brennan HJ
    4. Crimeen-Irwin B
    5. Poulton IJ
    6. Martin TJ
    7. Sims NA

    (2015) Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone

    Bone 81:343–351.

    https://doi.org/10.1016/j.bone.2015.08.005

    • PubMed
    • Google Scholar
67. 1. Kallin A
    2. Demoulin JB
    3. Nishida K
    4. Hirano T
    5. Rönnstrand L
    6. Heldin CH

    (2004) Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor

    The Journal of Biological Chemistry 279:17897–17904.

    https://doi.org/10.1074/jbc.M312996200

    • PubMed
    • Google Scholar
68. 1. Karsdal MA
    2. Martin TJ
    3. Bollerslev J
    4. Christiansen C
    5. Henriksen K

    (2007) Are nonresorbing osteoclasts sources of bone anabolic activity?

    Journal of Bone and Mineral Research 22:487–494.

    https://doi.org/10.1359/jbmr.070109

    • PubMed
    • Google Scholar
69. 1. Karsdal MA
    2. Neutzsky-Wulff AV
    3. Dziegiel MH
    4. Christiansen C
    5. Henriksen K

    (2008) Osteoclasts secrete non-bone derived signals that induce bone formation

    Biochemical and Biophysical Research Communications 366:483–488.

    https://doi.org/10.1016/j.bbrc.2007.11.168

    • PubMed
    • Google Scholar
70. 1. Katagiri T
    2. Watabe T

    (2016) Bone morphogenetic proteins

    Cold Spring Harbor Perspectives in Biology 8:a021899.

    https://doi.org/10.1101/cshperspect.a021899

    • PubMed
    • Google Scholar
71. 1. Kato G
    2. Shimizu Y
    3. Arai Y
    4. Suzuki N
    5. Sugamori Y
    6. Maeda M
    7. Takahashi M
    8. Tamura Y
    9. Wakabayashi N
    10. Murali R
    11. Ono T
    12. Ohya K
    13. Mise-Omata S
    14. Aoki K

    (2015) The inhibitory effects of a RANKL-binding peptide on articular and periarticular bone loss in a murine model of collagen-induced arthritis: a bone histomorphometric study

    Arthritis Research & Therapy 17:251.

    https://doi.org/10.1186/s13075-015-0753-8

    • PubMed
    • Google Scholar
72. 1. Kawaguchi H

    (2020) Serious adverse events with romosozumab use in japanese patients: Need for clear formulation of contraindications worldwide

    Journal of Bone and Mineral Research 35:994–995.

    https://doi.org/10.1002/jbmr.4001

    • PubMed
    • Google Scholar
73. 1. Keller H
    2. Kneissel M

    (2005) SOST is a target gene for PTH in bone

    Bone 37:148–158.

    https://doi.org/10.1016/j.bone.2005.03.018

    • PubMed
    • Google Scholar
74. 1. Keller J
    2. Catala-Lehnen P
    3. Huebner AK
    4. Jeschke A
    5. Heckt T
    6. Lueth A
    7. Krause M
    8. Koehne T
    9. Albers J
    10. Schulze J
    11. Schilling S
    12. Haberland M
    13. Denninger H
    14. Neven M
    15. Hermans-Borgmeyer I
    16. Streichert T
    17. Breer S
    18. Barvencik F
    19. Levkau B
    20. Rathkolb B
    21. Wolf E
    22. Calzada-Wack J
    23. Neff F
    24. Gailus-Durner V
    25. Fuchs H
    26. de Angelis MH
    27. Klutmann S
    28. Tsourdi E
    29. Hofbauer LC
    30. Kleuser B
    31. Chun J
    32. Schinke T
    33. Amling M

    (2014) Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

    Nature Communications 5:5215.

    https://doi.org/10.1038/ncomms6215

    • PubMed
    • Google Scholar
75. 1. Khan AA
    2. Sándor GKB
    3. Dore E
    4. Morrison AD
    5. Alsahli M
    6. Amin F
    7. Peters E
    8. Hanley DA
    9. Chaudry SR
    10. Lentle B
    11. Dempster DW
    12. Glorieux FH
    13. Neville AJ
    14. Talwar RM
    15. Clokie CM
    16. Mardini MA
    17. Paul T
    18. Khosla S
    19. Josse RG
    20. Sutherland S
    21. Lam DK
    22. Carmichael RP
    23. Blanas N
    24. Kendler D
    25. Petak S
    26. Ste-Marie LG
    27. Brown J
    28. Evans AW
    29. Rios L
    30. Compston JE

    (2009) Bisphosphonate associated osteonecrosis of the jaw

    The Journal of Rheumatology 36:478–490.

    https://doi.org/10.3899/jrheum.080759

    • PubMed
    • Google Scholar
76. 1. Kim B
    2. Huang G
    3. Ho WB
    4. Greenspan DS

    (2011) Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3

    The Journal of Biological Chemistry 286:29014–29025.

    https://doi.org/10.1074/jbc.M111.252585

    • PubMed
    • Google Scholar
77. 1. Kim BJ
    2. Lee YS
    3. Lee SY
    4. Park SY
    5. Dieplinger H
    6. Ryu SH
    7. Yea K
    8. Choi S
    9. Lee SH
    10. Koh JM
    11. Kim GS

    (2012) Afamin secreted from nonresorbing osteoclasts acts as a chemokine for preosteoblasts via the Akt-signaling pathway

    Bone 51:431–440.

    https://doi.org/10.1016/j.bone.2012.06.015

    • PubMed
    • Google Scholar
78. 1. Kim BJ
    2. Lee YS
    3. Lee SY
    4. Baek WY
    5. Choi YJ
    6. Moon SA
    7. Lee SH
    8. Kim JE
    9. Chang EJ
    10. Kim EY
    11. Yoon J
    12. Kim SW
    13. Ryu SH
    14. Lee SK
    15. Lorenzo JA
    16. Ahn SH
    17. Kim H
    18. Lee KU
    19. Kim GS
    20. Koh JM

    (2018) Osteoclast-secreted SLIT3 coordinates bone resorption and formation

    The Journal of Clinical Investigation 128:1429–1441.

    https://doi.org/10.1172/JCI91086

    • PubMed
    • Google Scholar
79. 1. Kim EY
    2. Kim JE
    3. Chung SH
    4. Park JE
    5. Yoon D
    6. Min HJ
    7. Sung Y
    8. Lee SB
    9. Kim SW
    10. Chang EJ

    (2023) Concomitant induction of SLIT3 and microRNA-218–2 in macrophages by toll-like receptor 4 activation limits osteoclast commitment

    Cell Communication and Signaling 21:1226-w.

    https://doi.org/10.1186/s12964-023-01226-w

    • Google Scholar
80. 1. Kimura H
    2. Kwan KM
    3. Zhang Z
    4. Deng JM
    5. Darnay BG
    6. Behringer RR
    7. Nakamura T
    8. de Crombrugghe B
    9. Akiyama H

    (2008) Cthrc1 is a positive regulator of osteoblastic bone formation

    PLOS ONE 3:e3174.

    https://doi.org/10.1371/journal.pone.0003174

    • PubMed
    • Google Scholar
81. 1. Kobayashi Y
    2. Thirukonda GJ
    3. Nakamura Y
    4. Koide M
    5. Yamashita T
    6. Uehara S
    7. Kato H
    8. Udagawa N
    9. Takahashi N

    (2015) Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a

    Biochemical and Biophysical Research Communications 463:1278–1283.

    https://doi.org/10.1016/j.bbrc.2015.06.102

    • PubMed
    • Google Scholar
82. 1. Koh JSB
    2. Goh SK
    3. Png MA
    4. Kwek EBK
    5. Howe TS

    (2010) Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture?

    Journal of Orthopaedic Trauma 24:75–81.

    https://doi.org/10.1097/BOT.0b013e3181b6499b

    • PubMed
    • Google Scholar
83. 1. Koohini Z
    2. Koohini Z
    3. Teimourian S

    (2019) Slit/robo signaling pathway in cancer; a new stand point for cancer treatment

    Pathology Oncology Research 25:1285–1293.

    https://doi.org/10.1007/s12253-018-00568-y

    • PubMed
    • Google Scholar
84. 1. Kramer SG
    2. Kidd T
    3. Simpson JH
    4. Goodman CS

    (2001) Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration

    Science 292:737–740.

    https://doi.org/10.1126/science.1058766

    • PubMed
    • Google Scholar
85. 1. Kreja L
    2. Brenner RE
    3. Tautzenberger A
    4. Liedert A
    5. Friemert B
    6. Ehrnthaller C
    7. Huber-Lang M
    8. Ignatius A

    (2010) Non-resorbing osteoclasts induce migration and osteogenic differentiation of mesenchymal stem cells

    Journal of Cellular Biochemistry 109:347–355.

    https://doi.org/10.1002/jcb.22406

    • PubMed
    • Google Scholar
86. 1. Krupa K
    2. Parmar M
    3. Delo LF

    (2023)

    StatPearls

    Romosozumab, StatPearls, StatPearls Publishing.

    • Google Scholar
87. 1. Kubota K
    2. Sakikawa C
    3. Katsumata M
    4. Nakamura T
    5. Wakabayashi K

    (2002) Platelet-derived growth factor BB secreted from osteoclasts acts as an osteoblastogenesis inhibitory factor

    Journal of Bone and Mineral Research 17:257–265.

    https://doi.org/10.1359/jbmr.2002.17.2.257

    • PubMed
    • Google Scholar
88. 1. LeClair R
    2. Lindner V

    (2007) The role of collagen triple helix repeat containing 1 in injured arteries, collagen expression, and transforming growth factor beta signaling

    Trends in Cardiovascular Medicine 17:202–205.

    https://doi.org/10.1016/j.tcm.2007.05.004

    • PubMed
    • Google Scholar
89. 1. Lewiecki EM
    2. Miller PD
    3. McClung MR
    4. Cohen SB
    5. Bolognese MA
    6. Liu Y
    7. Wang A
    8. Siddhanti S
    9. Fitzpatrick LA

    (2007) Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD

    Journal of Bone and Mineral Research 22:1832–1841.

    https://doi.org/10.1359/jbmr.070809

    • PubMed
    • Google Scholar
90. 1. Li D
    2. Liu J
    3. Guo B
    4. Liang C
    5. Dang L
    6. Lu C
    7. He X
    8. Cheung HY-S
    9. Xu L
    10. Lu C
    11. He B
    12. Liu B
    13. Shaikh AB
    14. Li F
    15. Wang L
    16. Yang Z
    17. Au DW-T
    18. Peng S
    19. Zhang Z
    20. Zhang B-T
    21. Pan X
    22. Qian A
    23. Shang P
    24. Xiao L
    25. Jiang B
    26. Wong CK-C
    27. Xu J
    28. Bian Z
    29. Liang Z
    30. Guo D-A
    31. Zhu H
    32. Tan W
    33. Lu A
    34. Zhang G

    (2016) Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation

    Nature Communications 7:10872.

    https://doi.org/10.1038/ncomms10872

    • PubMed
    • Google Scholar
91. 1. Li N
    2. Inoue K
    3. Sun J
    4. Niu Y
    5. Lalani S
    6. Yallowitz A
    7. Yang X
    8. Zhang C
    9. Shen R
    10. Zhao B
    11. Xu R
    12. Greenblatt MB

    (2020) Osteoclasts are not a source of SLIT3

    Bone Research 8:11.

    https://doi.org/10.1038/s41413-020-0086-3

    • PubMed
    • Google Scholar
92. 1. Lian JB
    2. Stein GS
    3. van Wijnen AJ
    4. Stein JL
    5. Hassan MQ
    6. Gaur T
    7. Zhang Y

    (2012) MicroRNA control of bone formation and homeostasis

    Nature Reviews. Endocrinology 8:212–227.

    https://doi.org/10.1038/nrendo.2011.234

    • PubMed
    • Google Scholar
93. 1. Liang M
    2. Yin X
    3. Zhang S
    4. Ai H
    5. Luo F
    6. Xu J
    7. Dou C
    8. Dong S
    9. Ma Q

    (2021) Osteoclast-derived small extracellular vesicles induce osteogenic differentiation via inhibiting ARHGAP1

    Molecular Therapy. Nucleic Acids 23:1191–1203.

    https://doi.org/10.1016/j.omtn.2021.01.031

    • PubMed
    • Google Scholar
94. 1. Lindsay R
    2. Krege JH
    3. Marin F
    4. Jin L
    5. Stepan JJ

    (2016) Teriparatide for osteoporosis: importance of the full course

    Osteoporosis International 27:2395–2410.

    https://doi.org/10.1007/s00198-016-3534-6

    • PubMed
    • Google Scholar
95. 1. Liu M
    2. Sun Y
    3. Zhang Q

    (2018) Emerging role of extracellular vesicles in bone remodeling

    Journal of Dental Research 97:859–868.

    https://doi.org/10.1177/0022034518764411

    • PubMed
    • Google Scholar
96. 1. Liu NQ
    2. Lin Y
    3. Li L
    4. Lu J
    5. Geng D
    6. Zhang J
    7. Jashashvili T
    8. Buser Z
    9. Magallanes J
    10. Tassey J
    11. Shkhyan R
    12. Sarkar A
    13. Lopez N
    14. Lee S
    15. Lee Y
    16. Wang L
    17. Petrigliano FA
    18. Van Handel B
    19. Lyons K
    20. Evseenko D

    (2022) gp130/STAT3 signaling is required for homeostatic proliferation and anabolism in postnatal growth plate and articular chondrocytes

    Communications Biology 5:64.

    https://doi.org/10.1038/s42003-021-02944-y

    • PubMed
    • Google Scholar
97. 1. Ljusberg J
    2. Wang Y
    3. Lång P
    4. Norgård M
    5. Dodds R
    6. Hultenby K
    7. Ek-Rylander B
    8. Andersson G

    (2005) Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts

    The Journal of Biological Chemistry 280:28370–28381.

    https://doi.org/10.1074/jbc.M502469200

    • PubMed
    • Google Scholar
98. 1. Lojk J
    2. Marc J

    (2021) Roles of non-canonical wnt signalling pathways in bone biology

    International Journal of Molecular Sciences 22:10840.

    https://doi.org/10.3390/ijms221910840

    • PubMed
    • Google Scholar
99. 1. López-Yoldi M
    2. Moreno-Aliaga MJ
    3. Bustos M

    (2015) Cardiotrophin-1: a multifaceted cytokine

    Cytokine & Growth Factor Reviews 26:523–532.

    https://doi.org/10.1016/j.cytogfr.2015.07.009

    • PubMed
    • Google Scholar
100. 1. Lotinun S
     2. Kiviranta R
     3. Matsubara T
     4. Alzate JA
     5. Neff L
     6. Lüth A
     7. Koskivirta I
     8. Kleuser B
     9. Vacher J
     10. Vuorio E
     11. Horne WC
     12. Baron R

     (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation

     The Journal of Clinical Investigation 123:666–681.

     https://doi.org/10.1172/JCI64840

     • PubMed
     • Google Scholar
101. 1. Lubbers R
     2. van Essen MF
     3. van Kooten C
     4. Trouw LA

     (2017) Production of complement components by cells of the immune system

     Clinical and Experimental Immunology 188:183–194.

     https://doi.org/10.1111/cei.12952

     • PubMed
     • Google Scholar
102. 1. Ma Q
     2. Liang M
     3. Wu Y
     4. Luo F
     5. Ma Z
     6. Dong S
     7. Xu J
     8. Dou C

     (2021) Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling

     Bone Research 9:5.

     https://doi.org/10.1038/s41413-020-00121-1

     • PubMed
     • Google Scholar
103. 1. Maeda K
     2. Kobayashi Y
     3. Udagawa N
     4. Uehara S
     5. Ishihara A
     6. Mizoguchi T
     7. Kikuchi Y
     8. Takada I
     9. Kato S
     10. Kani S
     11. Nishita M
     12. Marumo K
     13. Martin TJ
     14. Minami Y
     15. Takahashi N

     (2012) Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis

     Nature Medicine 18:405–412.

     https://doi.org/10.1038/nm.2653

     • PubMed
     • Google Scholar
104. 1. Marom R
     2. Rabenhorst BM
     3. Morello R

     (2020) Osteogenesis imperfecta: an update on clinical features and therapies

     European Journal of Endocrinology 183:R95–R106.

     https://doi.org/10.1530/EJE-20-0299

     • PubMed
     • Google Scholar
105. 1. Martin TJ

     (2004)

     Paracrine regulation of osteoclast formation and activity: milestones in discovery

     Journal of Musculoskeletal & Neuronal Interactions 4:243–253.

     • PubMed
     • Google Scholar
106. 1. Martin TJ
     2. Sims NA

     (2005) Osteoclast-derived activity in the coupling of bone formation to resorption

     Trends in Molecular Medicine 11:76–81.

     https://doi.org/10.1016/j.molmed.2004.12.004

     • PubMed
     • Google Scholar
107. 1. Marzella PL
     2. Gillespie LN
     3. Clark GM
     4. Bartlett PF
     5. Kilpatrick TJ

     (1999) The neurotrophins act synergistically with LIF and members of the TGF-beta superfamily to promote the survival of spiral ganglia neurons in vitro

     Hearing Research 138:73–80.

     https://doi.org/10.1016/s0378-5955(99)00152-5

     • PubMed
     • Google Scholar
108. 1. Matsuo K
     2. Irie N

     (2008) Osteoclast-osteoblast communication

     Archives of Biochemistry and Biophysics 473:201–209.

     https://doi.org/10.1016/j.abb.2008.03.027

     • PubMed
     • Google Scholar
109. 1. Matsuoka K
     2. Park KA
     3. Ito M
     4. Ikeda K
     5. Takeshita S

     (2014) Osteoclast-derived complement component 3a stimulates osteoblast differentiation

     Journal of Bone and Mineral Research 29:1522–1530.

     https://doi.org/10.1002/jbmr.2187

     • PubMed
     • Google Scholar
110. 1. Matsuoka K
     2. Kohara Y
     3. Naoe Y
     4. Watanabe A
     5. Ito M
     6. Ikeda K
     7. Takeshita S

     (2018) Waif1 is a cell-surface cthrc1 binding protein coupling bone resorption and formation

     Journal of Bone and Mineral Research 33:1500–1512.

     https://doi.org/10.1002/jbmr.3436

     • PubMed
     • Google Scholar
111. 1. McClung MR
     2. Lewiecki EM
     3. Cohen SB
     4. Bolognese MA
     5. Woodson GC
     6. Moffett AH
     7. Peacock M
     8. Miller PD
     9. Lederman SN
     10. Chesnut CH
     11. Lain D
     12. Kivitz AJ
     13. Holloway DL
     14. Zhang C
     15. Peterson MC
     16. Bekker PJ

     (2006) Denosumab in postmenopausal women with low bone mineral density

     The New England Journal of Medicine 354:821–831.

     https://doi.org/10.1056/NEJMoa044459

     • PubMed
     • Google Scholar
112. 1. Mendelson K
     2. Evans T
     3. Hla T

     (2014) Sphingosine 1-phosphate signalling

     Development 141:5–9.

     https://doi.org/10.1242/dev.094805

     • PubMed
     • Google Scholar
113. 1. Michalski MN
     2. Williams BO

     (2023) The past, present, and future of genetically engineered mouse models for skeletal biology

     Biomolecules 13:1311.

     https://doi.org/10.3390/biom13091311

     • PubMed
     • Google Scholar
114. 1. Miller SC
     2. Jee WS

     (1987) The bone lining cell: a distinct phenotype?

     Calcified Tissue International 41:1–5.

     https://doi.org/10.1007/BF02555122

     • PubMed
     • Google Scholar
115. 1. Mitlak BH
     2. Finkelman RD
     3. Hill EL
     4. Li J
     5. Martin B
     6. Smith T
     7. D’Andrea M
     8. Antoniades HN
     9. Lynch SE

     (1996) The effect of systemically administered PDGF-BB on the rodent skeleton

     Journal of Bone and Mineral Research 11:238–247.

     https://doi.org/10.1002/jbmr.5650110213

     • PubMed
     • Google Scholar
116. 1. Mohan S
     2. Thompson GR
     3. Amaar YG
     4. Hathaway G
     5. Tschesche H
     6. Baylink DJ

     (2002) ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts

     Biochemistry 41:15394–15403.

     https://doi.org/10.1021/bi026458q

     • PubMed
     • Google Scholar
117. 1. Mulari M
     2. Vääräniemi J
     3. Väänänen HK

     (2003) Intracellular membrane trafficking in bone resorbing osteoclasts

     Microscopy Research and Technique 61:496–503.

     https://doi.org/10.1002/jemt.10371

     • PubMed
     • Google Scholar
118. 1. Nash TJ
     2. Howlett CR
     3. Martin C
     4. Steele J
     5. Johnson KA
     6. Hicklin DJ

     (1994) Effect of platelet-derived growth factor on tibial osteotomies in rabbits

     Bone 15:203–208.

     https://doi.org/10.1016/8756-3282(94)90709-9

     • PubMed
     • Google Scholar
119. 1. Negishi-Koga T
     2. Shinohara M
     3. Komatsu N
     4. Bito H
     5. Kodama T
     6. Friedel RH
     7. Takayanagi H

     (2011) Suppression of bone formation by osteoclastic expression of semaphorin 4D

     Nature Medicine 17:1473–1480.

     https://doi.org/10.1038/nm.2489

     • PubMed
     • Google Scholar
120. 1. Negishi-Koga T
     2. Takayanagi H

     (2012) Bone cell communication factors and semaphorins

     BoneKEy Reports 1:183.

     https://doi.org/10.1038/bonekey.2012.183

     • PubMed
     • Google Scholar
121. 1. Nyman JS
     2. Yeh OC
     3. Hazelwood SJ
     4. Martin RB

     (2004) A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage

     Bone 35:296–305.

     https://doi.org/10.1016/j.bone.2004.03.007

     • PubMed
     • Google Scholar
122. 1. Ohtsuka M
     2. Sato M

     (2019) i-GONAD: A method for generating genome-edited animals without ex vivo handling of embryos

     Development, Growth & Differentiation 61:306–315.

     https://doi.org/10.1111/dgd.12620

     • PubMed
     • Google Scholar
123. 1. Okamoto M
     2. Murai J
     3. Imai Y
     4. Ikegami D
     5. Kamiya N
     6. Kato S
     7. Mishina Y
     8. Yoshikawa H
     9. Tsumaki N

     (2011) Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice

     Journal of Bone and Mineral Research 26:2511–2522.

     https://doi.org/10.1002/jbmr.477

     • PubMed
     • Google Scholar
124. 1. Oreffo RO
     2. Mundy GR
     3. Seyedin SM
     4. Bonewald LF

     (1989) Activation of the bone-derived latent TGF beta complex by isolated osteoclasts

     Biochemical and Biophysical Research Communications 158:817–823.

     https://doi.org/10.1016/0006-291x(89)92795-2

     • PubMed
     • Google Scholar
125. 1. O’Sullivan S
     2. Naot D
     3. Callon K
     4. Porteous F
     5. Horne A
     6. Wattie D
     7. Watson M
     8. Cornish J
     9. Browett P
     10. Grey A

     (2007) Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms

     Journal of Bone and Mineral Research 22:1679–1689.

     https://doi.org/10.1359/jbmr.070719

     • PubMed
     • Google Scholar
126. 1. Ota K
     2. Quint P
     3. Ruan M
     4. Pederson L
     5. Westendorf JJ
     6. Khosla S
     7. Oursler MJ

     (2013a) TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts

     Endocrinology 154:3745–3752.

     https://doi.org/10.1210/en.2013-1272

     • PubMed
     • Google Scholar
127. 1. Ota K
     2. Quint P
     3. Weivoda MM
     4. Ruan M
     5. Pederson L
     6. Westendorf JJ
     7. Khosla S
     8. Oursler MJ

     (2013b) Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors

     Bone 57:68–75.

     https://doi.org/10.1016/j.bone.2013.07.023

     • PubMed
     • Google Scholar
128. 1. Pasquale EB

     (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond

     Nature Reviews. Cancer 10:165–180.

     https://doi.org/10.1038/nrc2806

     • PubMed
     • Google Scholar
129. 1. Pederson L
     2. Ruan M
     3. Westendorf JJ
     4. Khosla S
     5. Oursler MJ

     (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate

     PNAS 105:20764–20769.

     https://doi.org/10.1073/pnas.0805133106

     • PubMed
     • Google Scholar
130. 1. Pennica D
     2. King KL
     3. Shaw KJ
     4. Luis E
     5. Rullamas J
     6. Luoh SM
     7. Darbonne WC
     8. Knutzon DS
     9. Yen R
     10. Chien KR

     (1995) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy

     PNAS 92:1142–1146.

     https://doi.org/10.1073/pnas.92.4.1142

     • PubMed
     • Google Scholar
131. 1. Peters M
     2. Roeb E
     3. Pennica D
     4. Meyer zum Büschenfelde KH
     5. Rose-John S

     (1995) A new hepatocyte stimulating factor: cardiotrophin-1 (CT-1)

     FEBS Letters 372:177–180.

     https://doi.org/10.1016/0014-5793(95)00972-c

     • PubMed
     • Google Scholar
132. 1. Phan TCA
     2. Xu J
     3. Zheng MH

     (2004) Interaction between osteoblast and osteoclast: impact in bone disease

     Histology and Histopathology 19:1325–1344.

     https://doi.org/10.14670/HH-19.1325

     • PubMed
     • Google Scholar
133. 1. Pietrzyk B
     2. Smertka M
     3. Chudek J

     (2017) Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

     Advances in Clinical and Experimental Medicine 26:1283–1291.

     https://doi.org/10.17219/acem/68739

     • PubMed
     • Google Scholar
134. 1. Portal-Núñez S
     2. Mediero A
     3. Esbrit P
     4. Sánchez-Pernaute O
     5. Largo R
     6. Herrero-Beaumont G

     (2017) Unexpected bone formation produced by rankl blockade

     Trends in Endocrinology and Metabolism 28:695–704.

     https://doi.org/10.1016/j.tem.2017.06.003

     • PubMed
     • Google Scholar
135. 1. Pyagay P
     2. Heroult M
     3. Wang Q
     4. Lehnert W
     5. Belden J
     6. Liaw L
     7. Friesel RE
     8. Lindner V

     (2005) Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration

     Circulation Research 96:261–268.

     https://doi.org/10.1161/01.RES.0000154262.07264.12

     • PubMed
     • Google Scholar
136. 1. Quint P
     2. Ruan M
     3. Pederson L
     4. Kassem M
     5. Westendorf JJ
     6. Khosla S
     7. Oursler MJ

     (2013) Sphingosine 1-phosphate (S1P) receptors 1 and 2 coordinately induce mesenchymal cell migration through S1P activation of complementary kinase pathways

     The Journal of Biological Chemistry 288:5398–5406.

     https://doi.org/10.1074/jbc.M112.413583

     • PubMed
     • Google Scholar
137. 1. Ransjö M
     2. Sahli J
     3. Lie A

     (2003) Expression of connexin 43 mRNA in microisolated murine osteoclasts and regulation of bone resorption in vitro by gap junction inhibitors

     Biochemical and Biophysical Research Communications 303:1179–1185.

     https://doi.org/10.1016/s0006-291x(03)00502-3

     • PubMed
     • Google Scholar
138. 1. Reyes C
     2. Hitz M
     3. Prieto-Alhambra D
     4. Abrahamsen B

     (2016) Risks and benefits of bisphosphonate therapies

     Journal of Cellular Biochemistry 117:20–28.

     https://doi.org/10.1002/jcb.25266

     • PubMed
     • Google Scholar
139. 1. Rhee J
     2. Buchan T
     3. Zukerberg L
     4. Lilien J
     5. Balsamo J

     (2007) Cables links Robo-bound Abl kinase to N-cadherin-bound beta-catenin to mediate Slit-induced modulation of adhesion and transcription

     Nature Cell Biology 9:883–892.

     https://doi.org/10.1038/ncb1614

     • PubMed
     • Google Scholar
140. 1. Rivera GM
     2. Antoku S
     3. Gelkop S
     4. Shin NY
     5. Hanks SK
     6. Pawson T
     7. Mayer BJ

     (2006) Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B

     PNAS 103:9536–9541.

     https://doi.org/10.1073/pnas.0603786103

     • PubMed
     • Google Scholar
141. 1. Roberts JL
     2. Liu G
     3. Paglia DN
     4. Kinter CW
     5. Fernandes LM
     6. Lorenzo J
     7. Hansen MF
     8. Arif A
     9. Drissi H

     (2020) Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation

     Annals of the New York Academy of Sciences 1463:45–59.

     https://doi.org/10.1111/nyas.14293

     • PubMed
     • Google Scholar
142. 1. Robling AG
     2. Castillo AB
     3. Turner CH

     (2006) Biomechanical and molecular regulation of bone remodeling

     Annual Review of Biomedical Engineering 8:455–498.

     https://doi.org/10.1146/annurev.bioeng.8.061505.095721

     • PubMed
     • Google Scholar
143. 1. Rogers MJ
     2. Crockett JC
     3. Coxon FP
     4. Mönkkönen J

     (2011) Biochemical and molecular mechanisms of action of bisphosphonates

     Bone 49:34–41.

     https://doi.org/10.1016/j.bone.2010.11.008

     • PubMed
     • Google Scholar
144. 1. Ross R
     2. Raines EW
     3. Bowen-Pope DF

     (1986) The biology of platelet-derived growth factor

     Cell 46:155–169.

     https://doi.org/10.1016/0092-8674(86)90733-6

     • PubMed
     • Google Scholar
145. 1. Ruiz P
     2. Martin-Millan M
     3. Gonzalez-Martin MC
     4. Almeida M
     5. González-Macias J
     6. Ros MA

     (2016) CathepsinKCre mediated deletion of βcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells

     Scientific Reports 6:36201.

     https://doi.org/10.1038/srep36201

     • PubMed
     • Google Scholar
146. 1. Russell RGG

     (2011) Bisphosphonates: the first 40years

     Bone 49:2–19.

     https://doi.org/10.1016/j.bone.2011.04.022

     • Google Scholar
147. 1. Ryu J
     2. Kim HJ
     3. Chang EJ
     4. Huang H
     5. Banno Y
     6. Kim HH

     (2006) Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling

     The EMBO Journal 25:5840–5851.

     https://doi.org/10.1038/sj.emboj.7601430

     • PubMed
     • Google Scholar
148. 1. Sanchez-Fernandez MA
     2. Gallois A
     3. Riedl T
     4. Jurdic P
     5. Hoflack B

     (2008) Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling

     PLOS ONE 3:e3537.

     https://doi.org/10.1371/journal.pone.0003537

     • PubMed
     • Google Scholar
149. 1. Sato T
     2. Hong MH
     3. Jin CH
     4. Ishimi Y
     5. Udagawa N
     6. Shinki T
     7. Abe E
     8. Suda T

     (1991) The specific production of the third component of complement by osteoblastic cells treated with 1 alpha,25-dihydroxyvitamin D3

     FEBS Letters 285:21–24.

     https://doi.org/10.1016/0014-5793(91)80715-f

     • PubMed
     • Google Scholar
150. 1. Sawa M
     2. Wakitani S
     3. Kamei N
     4. Kotaka S
     5. Adachi N
     6. Ochi M

     (2018) Local administration of WP9QY (W9) peptide promotes bone formation in a rat femur delayed-union model

     Journal of Bone and Mineral Metabolism 36:383–391.

     https://doi.org/10.1007/s00774-017-0852-5

     • PubMed
     • Google Scholar
151. 1. Seeman E

     (2003) Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis

     Osteoporosis International 14 Suppl 3:S2–S8.

     https://doi.org/10.1007/s00198-002-1340-9

     • PubMed
     • Google Scholar
152. 1. Segovia-Silvestre T
     2. Neutzsky-Wulff AV
     3. Sorensen MG
     4. Christiansen C
     5. Bollerslev J
     6. Karsdal MA
     7. Henriksen K

     (2009) Advances in osteoclast biology resulting from the study of osteopetrotic mutations

     Human Genetics 124:561–577.

     https://doi.org/10.1007/s00439-008-0583-8

     • PubMed
     • Google Scholar
153. 1. Shi K
     2. Lu J
     3. Zhao Y
     4. Wang L
     5. Li J
     6. Qi B
     7. Li H
     8. Ma C

     (2013) MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix

     Bone 55:487–494.

     https://doi.org/10.1016/j.bone.2013.04.002

     • PubMed
     • Google Scholar
154. 1. Shi C
     2. Zhang H
     3. Louie K
     4. Mishina Y
     5. Sun H

     (2017) Bmp signaling mediated by bmpr1a in osteoclasts negatively regulates osteoblast mineralization through suppression of cx43

     Journal of Cellular Biochemistry 118:605–614.

     https://doi.org/10.1002/jcb.25746

     • PubMed
     • Google Scholar
155. 1. Shin B
     2. Kupferman J
     3. Schmidt E
     4. Polleux F
     5. Delany AM
     6. Lee SK

     (2020) Rac1 inhibition via srgap2 restrains inflammatory osteoclastogenesis and limits the clastokine, slit3

     Journal of Bone and Mineral Research 35:789–800.

     https://doi.org/10.1002/jbmr.3945

     • PubMed
     • Google Scholar
156. 1. Silva BC
     2. Costa AG
     3. Cusano NE
     4. Kousteni S
     5. Bilezikian JP

     (2011) Catabolic and anabolic actions of parathyroid hormone on the skeleton

     Journal of Endocrinological Investigation 34:801–810.

     https://doi.org/10.3275/7925

     • PubMed
     • Google Scholar
157. 1. Sims NA
     2. Gooi JH

     (2008) Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption

     Seminars in Cell & Developmental Biology 19:444–451.

     https://doi.org/10.1016/j.semcdb.2008.07.016

     • PubMed
     • Google Scholar
158. 1. Sims NA
     2. Walsh NC

     (2010) GP130 cytokines and bone remodelling in health and disease

     BMB Reports 43:513–523.

     https://doi.org/10.5483/bmbrep.2010.43.8.513

     • PubMed
     • Google Scholar
159. 1. Sims NA
     2. Martin TJ

     (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit

     BoneKEy Reports 3:481.

     https://doi.org/10.1038/bonekey.2013.215

     • PubMed
     • Google Scholar
160. 1. Sims NA
     2. Martin TJ

     (2020) Osteoclasts provide coupling signals to osteoblast lineage cells through multiple mechanisms

     Annual Review of Physiology 82:507–529.

     https://doi.org/10.1146/annurev-physiol-021119-034425

     • PubMed
     • Google Scholar
161. 1. Spector JA
     2. Luchs JS
     3. Mehrara BJ
     4. Greenwald JA
     5. Smith LP
     6. Longaker MT

     (2001) Expression of bone morphogenetic proteins during membranous bone healing

     Plastic and Reconstructive Surgery 107:124–134.

     https://doi.org/10.1097/00006534-200101000-00018

     • PubMed
     • Google Scholar
162. 1. Stenbeck G

     (2002) Formation and function of the ruffled border in osteoclasts

     Seminars in Cell & Developmental Biology 13:285–292.

     https://doi.org/10.1016/s1084952102000587

     • PubMed
     • Google Scholar
163. 1. Sun B
     2. Chen B
     3. Zhao Y
     4. Sun W
     5. Chen K
     6. Zhang J
     7. Wei Z
     8. Xiao Z
     9. Dai J

     (2009) Crosslinking heparin to collagen scaffolds for the delivery of human platelet-derived growth factor

     Journal of Biomedical Materials Research. Part B, Applied Biomaterials 91:366–372.

     https://doi.org/10.1002/jbm.b.31411

     • PubMed
     • Google Scholar
164. 1. Sun W
     2. Zhao C
     3. Li Y
     4. Wang L
     5. Nie G
     6. Peng J
     7. Wang A
     8. Zhang P
     9. Tian W
     10. Li Q
     11. Song J
     12. Wang C
     13. Xu X
     14. Tian Y
     15. Zhao D
     16. Xu Z
     17. Zhong G
     18. Han B
     19. Ling S
     20. Chang YZ
     21. Li Y

     (2016) Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity

     Cell Discovery 2:16015.

     https://doi.org/10.1038/celldisc.2016.15

     • PubMed
     • Google Scholar
165. 1. Takasaki W
     2. Kajino Y
     3. Kajino K
     4. Murali R
     5. Greene MI

     (1997) Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor

     Nature Biotechnology 15:1266–1270.

     https://doi.org/10.1038/nbt1197-1266

     • PubMed
     • Google Scholar
166. 1. Takegahara N
     2. Kim H
     3. Choi Y

     (2022) RANKL biology

     Bone 159:116353.

     https://doi.org/10.1016/j.bone.2022.116353

     • PubMed
     • Google Scholar
167. 1. Takeshita S
     2. Fumoto T
     3. Matsuoka K
     4. Park K
     5. Aburatani H
     6. Kato S
     7. Ito M
     8. Ikeda K

     (2013) Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

     The Journal of Clinical Investigation 123:3914–3924.

     https://doi.org/10.1172/JCI69493

     • PubMed
     • Google Scholar
168. 1. Tang Y
     2. Wu X
     3. Lei W
     4. Pang L
     5. Wan C
     6. Shi Z
     7. Zhao L
     8. Nagy TR
     9. Peng X
     10. Hu J
     11. Feng X
     12. Van Hul W
     13. Wan M
     14. Cao X

     (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation

     Nature Medicine 15:757–765.

     https://doi.org/10.1038/nm.1979

     • PubMed
     • Google Scholar
169. 1. Thrailkill KM
     2. Quarles LD
     3. Nagase H
     4. Suzuki K
     5. Serra DM
     6. Fowlkes JL

     (1995) Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation

     Endocrinology 136:3527–3533.

     https://doi.org/10.1210/endo.136.8.7543045

     • PubMed
     • Google Scholar
170. 1. Tonna S
     2. Takyar FM
     3. Vrahnas C
     4. Crimeen-Irwin B
     5. Ho PWM
     6. Poulton IJ
     7. Brennan HJ
     8. McGregor NE
     9. Allan EH
     10. Nguyen H
     11. Forwood MR
     12. Tatarczuch L
     13. Mackie EJ
     14. Martin TJ
     15. Sims NA

     (2014) EphrinB2 signaling in osteoblasts promotes bone mineralization by preventing apoptosis

     FASEB Journal 28:4482–4496.

     https://doi.org/10.1096/fj.14-254300

     • PubMed
     • Google Scholar
171. 1. Törring O

     (2015) Effects of denosumab on bone density, mass and strength in women with postmenopausal osteoporosis

     Therapeutic Advances in Musculoskeletal Disease 7:88–102.

     https://doi.org/10.1177/1759720X15579189

     • Google Scholar
172. 1. Valenzuela JI
     2. Perez F

     (2020) Localized intercellular transfer of ephrin-as by trans-endocytosis enables long-term signaling

     Developmental Cell 52:104–117.

     https://doi.org/10.1016/j.devcel.2019.11.013

     • PubMed
     • Google Scholar
173. 1. van der Voort R
     2. van Lieshout AWT
     3. Toonen LWJ
     4. Slöetjes AW
     5. van den Berg WB
     6. Figdor CG
     7. Radstake T
     8. Adema GJ

     (2005) Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints

     Arthritis and Rheumatism 52:1381–1391.

     https://doi.org/10.1002/art.21004

     • PubMed
     • Google Scholar
174. 1. Walker EC
     2. McGregor NE
     3. Poulton IJ
     4. Pompolo S
     5. Allan EH
     6. Quinn JMW
     7. Gillespie MT
     8. Martin TJ
     9. Sims NA

     (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling

     Journal of Bone and Mineral Research 23:2025–2032.

     https://doi.org/10.1359/jbmr.080706

     • PubMed
     • Google Scholar
175. 1. Walker EC
     2. McGregor NE
     3. Poulton IJ
     4. Solano M
     5. Pompolo S
     6. Fernandes TJ
     7. Constable MJ
     8. Nicholson GC
     9. Zhang JG
     10. Nicola NA
     11. Gillespie MT
     12. Martin TJ
     13. Sims NA

     (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

     The Journal of Clinical Investigation 120:582–592.

     https://doi.org/10.1172/JCI40568

     • PubMed
     • Google Scholar
176. 1. Wang KH
     2. Brose K
     3. Arnott D
     4. Kidd T
     5. Goodman CS
     6. Henzel W
     7. Tessier-Lavigne M

     (1999) Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching

     Cell 96:771–784.

     https://doi.org/10.1016/s0092-8674(00)80588-7

     • PubMed
     • Google Scholar
177. 1. Wang X
     2. Guo B
     3. Li Q
     4. Peng J
     5. Yang Z
     6. Wang A
     7. Li D
     8. Hou Z
     9. Lv K
     10. Kan G
     11. Cao H
     12. Wu H
     13. Song J
     14. Pan X
     15. Sun Q
     16. Ling S
     17. Li Y
     18. Zhu M
     19. Zhang P
     20. Peng S
     21. Xie X
     22. Tang T
     23. Hong A
     24. Bian Z
     25. Bai Y
     26. Lu A
     27. Li Y
     28. He F
     29. Zhang G
     30. Li Y

     (2013) miR-214 targets ATF4 to inhibit bone formation

     Nature Medicine 19:93–100.

     https://doi.org/10.1038/nm.3026

     • PubMed
     • Google Scholar
178. 1. Wang L
     2. Liu S
     3. Zhao Y
     4. Liu D
     5. Liu Y
     6. Chen C
     7. Karray S
     8. Shi S
     9. Jin Y

     (2015) Osteoblast-induced osteoclast apoptosis by FAS ligand/FAS pathway is required for maintenance of bone mass

     Cell Death and Differentiation 22:1654–1664.

     https://doi.org/10.1038/cdd.2015.14

     • PubMed
     • Google Scholar
179. 1. Wang N
     2. Xue P
     3. Li Z
     4. Li Y

     (2018) IRS-1 increases TAZ expression and promotes osteogenic differentiation in rat bone marrow mesenchymal stem cells

     Biology Open 7:12.

     https://doi.org/10.1242/bio.036194

     • PubMed
     • Google Scholar
180. 1. Wang H
     2. He L
     3. Li Y
     4. Pu W
     5. Zhang S
     6. Han X
     7. Lui KO
     8. Zhou B

     (2022) Dual cre and dre recombinases mediate synchronized lineage tracing and cell subset ablation in vivo

     The Journal of Biological Chemistry 298:101965.

     https://doi.org/10.1016/j.jbc.2022.101965

     • PubMed
     • Google Scholar
181. 1. Watkins M
     2. Grimston SK
     3. Norris JY
     4. Guillotin B
     5. Shaw A
     6. Beniash E
     7. Civitelli R

     (2011) Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling

     Molecular Biology of the Cell 22:1240–1251.

     https://doi.org/10.1091/mbc.E10-07-0571

     • PubMed
     • Google Scholar
182. 1. Weivoda MM
     2. Chew CK
     3. Monroe DG
     4. Farr JN
     5. Atkinson EJ
     6. Geske JR
     7. Eckhardt B
     8. Thicke B
     9. Ruan M
     10. Tweed AJ
     11. McCready LK
     12. Rizza RA
     13. Matveyenko A
     14. Kassem M
     15. Andersen TL
     16. Vella A
     17. Drake MT
     18. Clarke BL
     19. Oursler MJ
     20. Khosla S

     (2020) Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism

     Nature Communications 11:003-6.

     https://doi.org/10.1038/s41467-019-14003-6

     • Google Scholar
183. 1. Wend P
     2. Wend K
     3. Krum SA
     4. Miranda-Carboni GA

     (2012) The role of WNT10B in physiology and disease

     Acta Physiologica 204:34–51.

     https://doi.org/10.1111/j.1748-1716.2011.02296.x

     • PubMed
     • Google Scholar
184. 1. Weske S
     2. Vaidya M
     3. Reese A
     4. von Wnuck Lipinski K
     5. Keul P
     6. Bayer JK
     7. Fischer JW
     8. Flögel U
     9. Nelsen J
     10. Epple M
     11. Scatena M
     12. Schwedhelm E
     13. Dörr M
     14. Völzke H
     15. Moritz E
     16. Hannemann A
     17. Rauch BH
     18. Gräler MH
     19. Heusch G
     20. Levkau B

     (2018) Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss

     Nature Medicine 24:667–678.

     https://doi.org/10.1038/s41591-018-0005-y

     • PubMed
     • Google Scholar
185. 1. Xi G
     2. Shen X
     3. Rosen CJ
     4. Clemmons DR

     (2019) Irs-1 functions as a molecular scaffold to coordinate igf-i/igfbp-2 signaling during osteoblast differentiation

     Journal of Bone and Mineral Research 34:2331.

     https://doi.org/10.1002/jbmr.3800

     • PubMed
     • Google Scholar
186. 1. Xian L
     2. Wu X
     3. Pang L
     4. Lou M
     5. Rosen CJ
     6. Qiu T
     7. Crane J
     8. Frassica F
     9. Zhang L
     10. Rodriguez JP

     (2012) Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells

     Nature Medicine 18:1095–1101.

     https://doi.org/10.1038/nm.2793

     • PubMed
     • Google Scholar
187. 1. Xu R
     2. Yallowitz A
     3. Qin A
     4. Wu Z
     5. Shin DY
     6. Kim JM
     7. Debnath S
     8. Ji G
     9. Bostrom MP
     10. Yang X
     11. Zhang C
     12. Dong H
     13. Kermani P
     14. Lalani S
     15. Li N
     16. Liu Y
     17. Poulos MG
     18. Wach A
     19. Zhang Y
     20. Inoue K
     21. Di Lorenzo A
     22. Zhao B
     23. Butler JM
     24. Shim JH
     25. Glimcher LH
     26. Greenblatt MB

     (2018) Targeting skeletal endothelium to ameliorate bone loss

     Nature Medicine 24:823–833.

     https://doi.org/10.1038/s41591-018-0020-z

     • PubMed
     • Google Scholar
188. 1. Zhang B
     2. Dietrich UM
     3. Geng JG
     4. Bicknell R
     5. Esko JD
     6. Wang L

     (2009) Repulsive axon guidance molecule Slit3 is a novel angiogenic factor

     Blood 114:4300–4309.

     https://doi.org/10.1182/blood-2008-12-193326

     • PubMed
     • Google Scholar
189. 1. Zhao C
     2. Irie N
     3. Takada Y
     4. Shimoda K
     5. Miyamoto T
     6. Nishiwaki T
     7. Suda T
     8. Matsuo K

     (2006) Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis

     Cell Metabolism 4:111–121.

     https://doi.org/10.1016/j.cmet.2006.05.012

     • PubMed
     • Google Scholar
190. 1. Zhao X
     2. Ma L
     3. Guo H
     4. Wang J
     5. Zhang S
     6. Yang X
     7. Yang L
     8. Jin Q

     (2022) Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis

     BMC Musculoskeletal Disorders 23:87.

     https://doi.org/10.1186/s12891-021-04886-2

     • PubMed
     • Google Scholar
191. 1. Zheng CM
     2. Hsu YH
     3. Wu CC
     4. Lu CL
     5. Liu WC
     6. Zheng JQ
     7. Lin YF
     8. Chiu HW
     9. Chang TJ
     10. Shyu JF
     11. Lu KC

     (2019) Osteoclast-released wnt-10b underlies cinacalcet related bone improvement in chronic kidney disease

     International Journal of Molecular Sciences 20:2800.

     https://doi.org/10.3390/ijms20112800

     • PubMed
     • Google Scholar
192. 1. Zhong Z
     2. Ethen NJ
     3. Williams BO

     (2014) WNT signaling in bone development and homeostasis

     Wiley Interdisciplinary Reviews. Developmental Biology 3:489–500.

     https://doi.org/10.1002/wdev.159

     • PubMed
     • Google Scholar

Author details

1. Valentina Daponte

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. VA Medical Center, Atlanta, United States

   Contribution

   Conceptualization, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8059-6283

2. Katrin Henke

   Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States

   Contribution

   Supervision, Writing - review and editing

   For correspondence

   khenke@emory.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1282-3616

3. Hicham Drissi

   1. Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States
   2. VA Medical Center, Atlanta, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Project administration, Writing - review and editing

   For correspondence

   hicham.drissi@emory.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3322-281X

• 1,386

  views

• 211

  downloads

• 4

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.